Immunopathobiology and therapeutic targets related to cytokines in liver diseases

Abstract

Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma. The progression of liver disease is controlled by a variety of factors, including liver injury, inflammatory cells, inflammatory mediators, cytokines, and the gut microbiome. In the current review, we discuss recent data on a large number of cytokines that play important roles in regulating liver injury, inflammation, fibrosis, and regeneration, with a focus on interferons and T helper (Th) 1, Th2, Th9, Th17, interleukin (IL)-1 family, IL-6 family, and IL-20 family cytokines. Hepatocytes can also produce certain cytokines (such as IL-7, IL-11, and IL-33), and the functions of these cytokines in the liver are briefly summarized. Several cytokines have great therapeutic potential, and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases, which are also described.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. 1.

    Asrani, S. K., Devarbhavi, H., Eaton, J. & Kamath, P. S. Burden of liver diseases in the world. J. Hepatol. 70, 151–171 (2019).

    PubMed  Article  Google Scholar 

  2. 2.

    Paik, J. M., Golabi, P., Younossi, Y., Mishra, A., Younossi, Z. M. Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of nonalcoholic fatty liver disease. Hepatology (2020). in press, https://doi.org/10.1002/hep.31173.

  3. 3.

    Crabb, D. W., Im, G. Y., Szabo, G., Mellinger, J. L. & Lucey, M. R. Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases. Hepatology 71, 306–333 (2020).

    PubMed  Article  Google Scholar 

  4. 4.

    Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Liaskou, E., Hirschfield, G. M. & Gershwin, M. E. Mechanisms of tissue injury in autoimmune liver diseases. Semin. Immunopathol. 36, 553–568 (2014).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Gao, B., Ahmad, M. F., Nagy, L. E. & Tsukamoto, H. Inflammatory pathways in alcoholic steatohepatitis. J. Hepatol. 70, 249–259 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Koyama, Y. & Brenner, D. A. Liver inflammation and fibrosis. J. Clin. Investig. 127, 55–64 (2017).

    PubMed  Article  Google Scholar 

  8. 8.

    Wree, A., Holtmann, T. M., Inzaugarat, M. E. & Feldstein, A. E. Novel drivers of the inflammatory response in liver injury and fibrosis. Semin. Liver Dis. 39, 275–282 (2019).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Radaeva, S. et al. Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes. Gastroenterology 122, 1020–1034 (2002).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Hermant, P. et al. Human but not mouse hepatocytes respond to interferon-lambda in vivo. PLoS ONE 9, e87906 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Koestner, W. et al. Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice. PLoS Pathog. 14, e1007235 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Lercher, A. et al. Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function. Immunity 51, 1074–1087 e9 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Eslam, M., Ahlenstiel, G. & George, J. Interferon lambda and liver fibrosis. J. Interferon Cytokine Res. 39, 627–635 (2019).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Eslam, M. et al. Interferon-lambda rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat. Commun. 6, 6422 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Wei, J. et al. SNX8 mediates IFNgamma-triggered noncanonical signaling pathway and host defense against Listeria monocytogenes. Proc. Natl Acad. Sci. USA 114, 13000–13005 (2017).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Chen, Y., Hao, X., Sun, R., Wei, H. & Tian, Z. Natural killer cell-derived interferon-gamma promotes hepatocellular carcinoma through the epithelial cell adhesion molecule-epithelial-to-mesenchymal transition axis in hepatitis B virus transgenic mice. Hepatology 69, 1735–1750 (2019).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Kalathil, S. G., Hutson, A., Barbi, J., Iyer, R. & Thanavala, Y. Augmentation of IFN-gamma+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy. JCI Insight 4, e130116 (2019).

    PubMed Central  Article  PubMed  Google Scholar 

  19. 19.

    Zeng, Z. et al. Interferon-gamma facilitates hepatic antiviral T cell retention for the maintenance of liver-induced systemic tolerance. J. Exp. Med. 213, 1079–1093 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Wang, H. et al. TNF-alpha/IFN-gamma profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection. J. Hepatol. 72, 45–56 (2020).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Bae, H. R. et al. Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology 64, 1189–1201 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Ravichandran, G. et al. Interferon-gamma-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. J. Hepatol. 71, 773–782 (2019).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Glaser, F. et al. Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis. J. Hepatol. 71, 783–792 (2019).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Radaeva, S. et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 130, 435–452 (2006).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Jeong, W. I., Park, O., Radaeva, S. & Gao, B. STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology 44, 1441–1451 (2006).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Weng, H., Mertens, P. R., Gressner, A. M. & Dooley, S. IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads. J. Hepatol. 46, 295–303 (2007).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Gao, B. Cytokines, STATs and liver disease. Cell Mol. Immunol. 2, 92–100 (2005).

    CAS  PubMed  Google Scholar 

  28. 28.

    He, X. et al. MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor. Proc. Natl Acad. Sci. USA 115, 180–185 (2018).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Tosello-Trampont, A. C. et al. NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 63, 799–812 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Hart, K. M. et al. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-beta. Sci. Transl. Med. 9, eaal3694 (2017).

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Xiang, X. et al. Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice. J. Hepatol. 72, 736–745 (2020).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Wallach, D. et al. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17, 331–367 (1999).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Boetticher, N. C. et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 135, 1953–1960 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Su, L. et al. Kupffer cell-derived TNF-alpha promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells. Cell Death Dis. 9, 323 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Hwang, S. et al. Protective and detrimental roles of p38alpha MAPK in different stages of nonalcoholic fatty liver disease. Hepatology 72, 873–891 (2020).

  36. 36.

    Hwang, S. et al. Interleukin-22 ameliorates neutrophil-driven nonalcoholic steatohepatitis through multiple targets. Hepatology 72, 412–429 (2019).

    Article  CAS  Google Scholar 

  37. 37.

    Choi, Y. S. et al. Tumor necrosis factor-producing T-regulatory cells are associated with severe liver injury in patients with acute hepatitis A. Gastroenterology 154, 1047–1060 (2018).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Li, X. F. et al. Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology 66, 1934–1951 (2017).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Tan, W. et al. TNF-alpha is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. EBioMedicine 40, 446–456 (2019).

    PubMed  Article  Google Scholar 

  40. 40.

    Tait Wojno, E. D., Hunter, C. A. & Stumhofer, J. S. The immunobiology of the interleukin-12 family: room for discovery. Immunity 50, 851–870 (2019).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Hou, X. et al. CD205-TLR9-IL-12 axis contributes to CpG-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells. Cell Mol. Immunol. 14, 675–684 (2017).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Dias, J. et al. Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells. J. Hepatol. 71, 301–312 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Heymann, F. & Tacke, F. Immunology in the liver-from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Everts, B. et al. Migratory CD103+ dendritic cells suppress helminth-driven type 2 immunity through constitutive expression of IL-12. J. Exp. Med. 213, 35–51 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Liberal, R. et al. Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis. Hepatology 66, 1570–1584 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Schwinge, D. et al. Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related to IL-12 signaling. J. Hepatol. 66, 798–805 (2017).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Busato, D. et al. Novel immunotherapeutic approaches for hepatocellular carcinoma treatment. Expert Rev. Clin. Pharmacol. 12, 453–470 (2019).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Liu, Y. et al. Armored inducible expression of IL-12 enhances antitumor activity of glypican-3-targeted chimeric antigen receptor-engineered T cells in hepatocellular carcinoma. J. Immunol. 203, 198–207 (2019).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Tan, X. et al. Elevated hepatic CD1d levels coincide with invariant NKT cell defects in chronic hepatitis B virus infection. J. Immunol. 200, 3530–3538 (2018).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Salimzadeh, L. et al. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J. Clin. Investig. 128, 4573–4587 (2018).

    PubMed  Article  Google Scholar 

  52. 52.

    Pallett, L. J. et al. IL-2(high) tissue-resident T cells in the human liver: sentinels for hepatotropic infection. J. Exp. Med. 214, 1567–1580 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Wing, K. & Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 11, 7–13 (2010).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Klatzmann, D. & Abbas, A. K. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat. Rev. Immunol. 15, 283–294 (2015).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Liberal, R. et al. In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression. Hepatology 62, 863–875 (2015).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Taubert, R. et al. Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J. Hepatol. 61, 1106–1114 (2014).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Jeffery, H. C. et al. Low-dose interleukin-2 promotes STAT-5 phosphorylation, Treg survival and CTLA-4-dependent function in autoimmune liver diseases. Clin. Exp. Immunol. 188, 394–411 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Taylor, A. E. et al. Interleukin 2 promotes hepatic regulatory T cell responses and protects from biliary fibrosis in murine sclerosing cholangitis. Hepatology 68, 1905–1921 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Gu, J. et al. Human CD39(hi) regulatory T cells present stronger stability and function under inflammatory conditions. Cell Mol. Immunol. 14, 521–528 (2017).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Bao, K. & Reinhardt, R. L. The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 75, 25–37 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    McCormick, S. M. & Heller, N. M. Commentary: IL-4 and IL-13 receptors and signaling. Cytokine 75, 38–50 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Ouyang, W. et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12, 27–37 (2000).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Ramsay, N. K. & Kersey, J. H. Indications for marrow transplantation in acute lymphoblastic leukemia. Blood 75, 815–818 (1990).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Zheng, T. et al. IL-13 receptor alpha2 selectively inhibits IL-13-induced responses in the murine lung. J. Immunol. 180, 522–529 (2008).

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R. K. & Kitani, A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat. Med. 12, 99–106 (2006).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Gieseck, R. L. 3rd, Wilson, M. S. & Wynn, T. A. Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol. 18, 62–76 (2018).

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Cordero-Espinoza, L. & Huch, M. The balancing act of the liver: tissue regeneration versus fibrosis. J. Clin. Investig 128, 85–96 (2018).

    PubMed  Article  Google Scholar 

  70. 70.

    Pearce, E. J. & MacDonald, A. S. The immunobiology of schistosomiasis. Nat. Rev. Immunol. 2, 499–511 (2002).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    He, X. et al. Recombinant adeno-associated virus-mediated inhibition of microRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and transforming growth factor beta 1 pathways. Hepatology 61, 2008–2017 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Gieseck, R. L. 3rd et al. Interleukin-13 activates distinct cellular pathways leading to ductular reaction, steatosis, and fibrosis. Immunity 45, 145–158 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    McDaniel, K. et al. Amelioration of ductular reaction by stem cell derived extracellular vesicles in MDR2 knockout mice via lethal-7 microRNA. Hepatology 69, 2562–2578 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Hahn, L. et al. IL-13 as target to reduce cholestasis and dysbiosis in Abcb4 knockout mice. Cells 9, 1949 (2020).

    PubMed Central  Article  PubMed  Google Scholar 

  75. 75.

    Walker, J. A. & McKenzie, A. N. J. TH2 cell development and function. Nat. Rev. Immunol. 18, 121–133 (2018).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity 32, 593–604 (2010).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Su, S. et al. miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program. Nat. Commun. 6, 8523 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Wang, M. et al. Role of gp91(phox) in hepatic macrophage programming and alcoholic liver disease. Hepatol. Commun. 1, 765–779 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Goh, Y. P. et al. Eosinophils secrete IL-4 to facilitate liver regeneration. Proc. Natl Acad. Sci. USA 110, 9914–9919 (2013).

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Yeung, O. W. et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J. Hepatol. 62, 607–616 (2015).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Zhu, Y. et al. Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Gut 68, 1653–1666 (2019).

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Brunner, S. M. et al. Tumor-infiltrating, interleukin-33-producing effector-memory CD8(+) T cells in resected hepatocellular carcinoma prolong patient survival. Hepatology 61, 1957–1967 (2015).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Jin, Z. et al. IL-33 released in the liver inhibits tumor growth via promotion of CD4(+) and CD8(+) T cell responses in hepatocellular carcinoma. J. Immunol. 201, 3770–3779 (2018).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Yu, S. J. et al. Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J. Hepatol. 70, 449–457 (2019).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Pelaia, C. et al. Interleukin-5 in the pathophysiology of severe asthma. Front Physiol. 10, 1514 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Molfino, N. A., Gossage, D., Kolbeck, R., Parker, J. M. & Geba, G. P. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin. Exp. Allergy 42, 712–737 (2012).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Pelaia, C. et al. Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab. Drug Des. Devel Ther. 11, 3137–3144 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Schwartz, C. et al. Eosinophil-specific deletion of IκBα in mice reveals a critical role of NF-κB-induced Bcl-xL for inhibition of apoptosis. Blood 125, 3896–3904 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Tiegs, G., Hentschel, J. & Wendel, A. A. T cell-dependent experimental liver injury in mice inducible by concanavalin A. J. Clin. Investig. 90, 196–203 (1992).

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Neumann, K. et al. A proinflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis. J. Immunol. 198, 128–137 (2017).

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Liu, Z. X., Govindarajan, S., Okamoto, S. & Dennert, G. Fas- and tumor necrosis factor receptor 1-dependent but not perforin-dependent pathways cause injury in livers infected with an adenovirus construct in mice. Hepatology 31, 665–673 (2000).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Peng, H. et al. IL-33 contributes to schistosoma japonicum-induced hepatic pathology through induction of M2 macrophages. Sci. Rep. 6, 29844 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Sanches, R. C. O. et al. NLRP6 plays an important role in early hepatic immunopathology caused by Schistosoma mansoni infection. Front. Immunol. 11, 795 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Kaplan, M. H., Hufford, M. M. & Olson, M. R. The development and in vivo function of T helper 9 cells. Nat. Rev. Immunol. 15, 295–307 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Nowak, E. C. et al. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med. 206, 1653–1660 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Townsend, J. M. et al. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13, 573–583 (2000).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Jäger, A., Dardalhon, V., Sobel, R. A., Bettelli, E. & Kuchroo, V. K. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol. 183, 7169–7177 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Elyaman, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl Acad. Sci. USA 106, 12885–12890 (2009).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Lu, Y. et al. Th9 cells promote antitumor immune responses in vivo. J. Clin. Investig 122, 4160–4171 (2012).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Clark, R. A. & Schlapbach, C. T(H)9 cells in skin disorders. Semin Immunopathol. 39, 47–54 (2017).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Koch, S., Sopel, N. & Finotto, S. Th9 and other IL-9-producing cells in allergic asthma. Semin Immunopathol. 39, 55–68 (2017).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Guo, X., Cen, Y., Wang, J. & Jiang, H. CXCL10-induced IL-9 promotes liver fibrosis via Raf/MEK/ERK signaling pathway. Biomed. Pharmacother. 105, 282–289 (2018).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Barsoum, R. S., Esmat, G. & El-Baz, T. Human schistosomiasis: clinical perspective: review. J. Adv. Res. 4, 433–444 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Li, L. et al. Characteristics of IL-9 induced by Schistosoma japonicum infection in C57BL/6 mouse liver. Sci. Rep. 7, 2343 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    Zhan, T. et al. Interleukin-9 blockage reduces early hepatic granuloma formation and fibrosis during Schistosoma japonicum infection in mice. Immunology 158, 296–303 (2019).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Pang, N. et al. TGF-β/Smad signaling pathway positively up-regulates the differentiation of Interleukin-9-producing CD4(+) T cells in human Echinococcus granulosus infection. J. Infect. 76, 406–416 (2018).

    PubMed  Article  Google Scholar 

  107. 107.

    Qin, S. Y. et al. A deleterious role for Th9/IL-9 in hepatic fibrogenesis. Sci. Rep. 6, 18694 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Yu, X. et al. Serum interleukin (IL)-9 and IL-10, but not T-helper 9 (Th9) cells, are associated with survival of patients with acute-on-chronic hepatitis B liver failure. Medicine 95, e3405 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Ali, M. E. et al. Role of T-helper 9 cells in chronic hepatitis C-infected patients. Viruses 10, 341 (2018).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  110. 110.

    Schmitt, E. & Bopp, T. Amazing IL-9: revealing a new function for an “old” cytokine. J. Clin. Invest 122, 3857–3859 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Tan, H., Wang, S. & Zhao, L. A tumour-promoting role of Th9 cells in hepatocellular carcinoma through CCL20 and STAT3 pathways. Clin. Exp. Pharmacol. Physiol. 44, 213–221 (2017).

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Meng, F. et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765–776 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Kolls, J. K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Iwakura, Y., Ishigame, H., Saijo, S. & Nakae, S. Functional specialization of interleukin-17 family members. Immunity 34, 149–162 (2011).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Gaffen, S. L. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol. 9, 556–567 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Lemmers, A. et al. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 49, 646–657 (2009).

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Lafdil, F., Miller, A. M., Ki, S. H. & Gao, B. Th17 cells and their associated cytokines in liver diseases. Cell Mol. Immunol. 7, 250–254 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Diveu, C. et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 182, 5748–5756 (2009).

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Hall, A. O., Silver, J. S. & Hunter, C. A. The immunobiology of IL-27. Adv. Immunol. 115, 1–44 (2012).

    PubMed  Article  CAS  Google Scholar 

  121. 121.

    Liu, Y., Munker, S., Mullenbach, R. & Weng, H. L. IL-13 signaling in liver fibrogenesis. Front Immunol. 3, 116 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Kleinschek, M. A. et al. IL-25 regulates Th17 function in autoimmune inflammation. J. Exp. Med 204, 161–170 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Yao, Z. et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811–821 (1995).

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Andoh, A. et al. IL-17 selectively down-regulates TNF-alpha-induced RANTES gene expression in human colonic subepithelial myofibroblasts. J. Immunol. 169, 1683–1687 (2002).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Moore, E. E. et al. Expression of IL-17B in neurons and evaluation of its possible role in the chromosome 5q-linked form of Charcot-Marie-Tooth disease. Neuromuscul. Disord. 12, 141–150 (2002).

    PubMed  Article  Google Scholar 

  127. 127.

    Yamaguchi, Y. et al. IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J. Immunol. 179, 7128–7136 (2007).

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Starnes, T., Broxmeyer, H. E., Robertson, M. J. & Hromas, R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J. Immunol. 169, 642–646 (2002).

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Seelige, R., Washington, A. Jr & Bui, J. D. The ancient cytokine IL-17D is regulated by Nrf2 and mediates tumor and virus surveillance. Cytokine 91, 10–12 (2017).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med 206, 35–41 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Lee, J. et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J. Biol. Chem. 276, 1660–1664 (2001).

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Rickel, E. A. et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J. Immunol. 181, 4299–4310 (2008).

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Liu, C. et al. A CC’ loop decoy peptide blocks the interaction between Act1 and IL-17RA to attenuate IL-17- and IL-25-induced inflammation. Sci. Signal 4, ra72 (2011).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Giles, D. A. et al. Regulation of inflammation by IL-17A and IL-17F modulates non-alcoholic fatty liver disease pathogenesis. PLoS ONE 11, e0149783 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. 135.

    von Vietinghoff, S. & Ley, K. IL-17A controls IL-17F production and maintains blood neutrophil counts in mice. J. Immunol. 183, 865–873 (2009).

    Article  CAS  Google Scholar 

  136. 136.

    Ma, H. Y. et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J. Hepatol. 72, 946–959 (2020).

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Xu, J. et al. Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice. JCI Insight 5, e131277 (2020).

    PubMed Central  Article  PubMed  Google Scholar 

  138. 138.

    Ortiz, M. L. et al. Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells. J. Exp. Med. 212, 351–367 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Gomes, A. L. et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30, 161–175 (2016).

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Giles, D. A. et al. Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. Nat. Med. 23, 829–838 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Seo, W. et al. Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by gammadelta T cells in liver fibrosis. Hepatology 64, 616–631 (2016).

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Lee, J. H. et al. Mitochondrial double-stranded RNA in exosome promotes interleukin-17 production through toll-like receptor 3 in alcohol-associated liver injury. Hepatology 72, 609–625 (2020).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Kim, J. Y. et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell 175, 133–145 e15 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Ikonen, E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. 9, 125–138 (2008).

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Osborne, T. F. & Espenshade, P. J. Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it’s been. Genes Dev. 23, 2578–2591 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Fitzky, B. U. et al. 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J. Clin. Investig. 108, 905–915 (2001).

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Yu, H. et al. Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. BMC Dev. Biol. 7, 27 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. 148.

    Yu, H., Wessels, A., Tint, G. S. & Patel, S. B. Partial rescue of neonatal lethality of Dhcr7 null mice by a nestin promoter-driven DHCR7 transgene expression. Brain Res. Dev. Brain Res. 156, 46–60 (2005).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Boland, M. R. & Tatonetti, N. P. Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. Pharmacogenomics J. 16, 411–429 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Solt, L. A. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472, 491–494 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Ma, H. Y. et al. The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in alcoholic liver disease. Curr. Pathobiol. Rep. 4, 27–35 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Pascual, M., Balino, P., Aragon, C. M. & Guerri, C. Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: role of TLR4 and TLR2. Neuropharmacology 89, 352–359 (2015).

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Chan, A. H. & Schroder, K. Inflammasome signaling and regulation of interleukin-1 family cytokines. J. Exp. Med. 217, e20190314 (2020).

    PubMed  Article  CAS  Google Scholar 

  155. 155.

    Mantovani, A., Dinarello, C. A., Molgora, M. & Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50, 778–795 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Negash, A. A. et al. IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog. 9, e1003330 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Dinarello, C. A. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol. Rev. 281, 8–27 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Tilg, H., Moschen, A. R. & Szabo, G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 64, 955–965 (2016).

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Tsutsui, H., Cai, X. & Hayashi, S. Interleukin-1 family cytokines in liver diseases. Mediators Inflamm. 2015, 630265 (2015).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Kamari, Y. et al. Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J. Hepatol. 55, 1086–1094 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Almog, T. et al. Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice. BMJ Open Diabetes Res. Care 7, e000650 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Olteanu, S. et al. Lack of interleukin-1α in Kupffer cells attenuates liver inflammation and expression of inflammatory cytokines in hypercholesterolaemic mice. Dig. Liver Dis. 46, 433–439 (2014).

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Pan, J. et al. Fatty acid activates NLRP3 inflammasomes in mouse Kupffer cells through mitochondrial DNA release. Cell Immunol. 332, 111–120 (2018).

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Mirea, A. M. et al. Mice Deficient in the IL-1β activation genes Prtn3, Elane, and Casp1 are protected against the development of obesity-induced NAFLD. Inflammation 43, 1054–1064 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Cazanave, S. et al. The transcriptomic signature of disease development and progression of nonalcoholic fatty liver disease. Sci. Rep. 7, 17193 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. 166.

    Xu, B. et al. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J. Hepatol. 68, 773–782 (2018).

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Palomera, L. F. et al. Serum levels of interleukin-1 beta associate better with severity of simple steatosis than liver function tests in morbidly obese patients. J. Res. Med. Sci. 23, 93 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Yamanishi, K. et al. Interleukin-18-deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease and steatohepatitis. Transl. Res. 173, 101–114.e7 (2016).

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Murphy, A. J. et al. IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. Cell Metab. 23, 155–164 (2016).

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Flisiak-Jackiewicz, M. et al. Predictive role of interleukin-18 in liver steatosis in obese children. Can. J. Gastroenterol. Hepatol. 2018, 3870454 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Yasuda, K., Nakanishi, K. & Tsutsui, H. Interleukin-18 in health and disease. Int. J. Mol. Sci. 20, 649 (2019).

  173. 173.

    McKie, E. A. et al. A study to investigate the efficacy and safety of an anti-interleukin-18 monoclonal antibody in the treatment of type 2 diabetes mellitus. PLoS ONE 11, e0150018 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  174. 174.

    Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Cai, C. et al. NLRP3 deletion inhibits the non-alcoholic steatohepatitis development and inflammation in Kupffer cells induced by palmitic acid. Inflammation 40, 1875–1883 (2017).

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Yang, G., Lee, H. E. & Lee, J. Y. A pharmacological inhibitor of NLRP3 inflammasome prevents non-alcoholic fatty liver disease in a mouse model induced by high fat diet. Sci. Rep. 6, 24399 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med 356, 1517–1526 (2007).

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J. Am. Coll. Cardiol. 71, 2392–2401 (2018).

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Vasseur, P. et al. Endogenous IL-33 has no effect on the progression of fibrosis during experimental steatohepatitis. Oncotarget 8, 48563–48574 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Gao, Y. et al. IL-33 treatment attenuated diet-induced hepatic steatosis but aggravated hepatic fibrosis. Oncotarget 7, 33649–33661 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Giannoudaki, E. et al. Interleukin-36 cytokines alter the intestinal microbiome and can protect against obesity and metabolic dysfunction. Nat. Commun. 10, 4003 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  182. 182.

    Ballak, D. B. et al. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 4711 (2014).

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Petrasek, J. et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J. Clin. Investig. 122, 3476–3489 (2012).

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Petrasek, J. et al. Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease. J. Leukoc. Biol. 98, 249–256 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Voican, C. S. et al. Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease. Liver Int. 35, 967–978 (2015).

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Cui, K. et al. Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice. J. Hepatol. 62, 1311–1318 (2015).

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Gyongyosi, B. et al. Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice. Mucosal Immunol. 12, 930–944 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Khanova, E. et al. Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67, 1737–1753 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Iracheta-Vellve, A. et al. Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice. Liver Int. 37, 968–973 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. 190.

    NIH U.S. National Library of Medicine. ClinicalTrials.gov. Efficacy Study of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis. https://clinicaltrials.gov/ct2/show/NCT01809132.

  191. 191.

    McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    Marvie, P. et al. Interleukin-33 overexpression is associated with liver fibrosis in mice and humans. J. Cell Mol. Med. 14, 1726–1739 (2010).

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Sun, Z. et al. Plasma levels of soluble ST2, but not IL-33, correlate with the severity of alcoholic liver disease. J. Cell Mol. Med. 23, 887–897 (2019).

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    Artru, F. et al. IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis. J. Hepatol. 72, 1052–1061 (2020).

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    Grabherr, F. et al. Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease. Liver Int 38, 1095–1101 (2018).

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Gieling, R. G., Wallace, K. & Han, Y. P. Interleukin-1 participates in the progression from liver injury to fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1324–G1331 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Wree, A. et al. NLRP3 inflammasome driven liver injury and fibrosis: Roles of IL-17 and TNF in mice. Hepatology 67, 736–749 (2018).

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Meier, R. P. H. et al. Interleukin-1 receptor antagonist modulates liver inflammation and fibrosis in mice in a model-dependent manner. Int J. Mol. Sci. 20, 1295 (2019).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  199. 199.

    Monteiro, S. et al. Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation. Gut (2020). in press, https://doi.org/10.1136/gutjnl-2019-320170.

  200. 200.

    Kotsiou, O. S., Gourgoulianis, K. I. & Zarogiannis, S. G. IL-33/ST2 axis in organ fibrosis. Front Immunol. 9, 2432 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. 201.

    Tan, Z. et al. Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells. Cell Mol. Immunol. 15, 388–398 (2018).

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Sultan, M. et al. Interleukin-1α and Interleukin-1β play a central role in the pathogenesis of fulminant hepatic failure in mice. PLoS ONE 12, e0184084 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  203. 203.

    Gehrke, N. et al. Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation. J. Hepatol. 68, 986–995 (2018).

    CAS  PubMed  Article  Google Scholar 

  204. 204.

    Zhang, C. et al. Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cell Mol. Immunol. 15, 973–982 (2018).

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    Bachmann, M., Pfeilschifter, J. & Mühl, H. A prominent role of interleukin-18 in acetaminophen-induced liver injury advocates its blockage for therapy of hepatic necroinflammation. Front. Immunol. 9, 161 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  206. 206.

    Castillo-Dela Cruz, P. et al. Intestinal IL-17R signaling constrains IL-18-driven liver inflammation by the regulation of microbiome-derived products. Cell Rep. 29, 2270–2283.e7 (2019).

    CAS  PubMed  Article  Google Scholar 

  207. 207.

    Antunes, M. M. et al. IL-33 signalling in liver immune cells enhances drug-induced liver injury and inflammation. Inflamm. Res. 67, 77–88 (2018).

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Yazdani, H. O. et al. IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation. J. Hepatol. 68, 130–139 (2018).

  209. 209.

    Scheiermann, P. et al. Application of IL-36 receptor antagonist weakens CCL20 expression and impairs recovery in the late phase of murine acetaminophen-induced liver injury. Sci. Rep. 5, 8521 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Feng, X. X. et al. IL-37 suppresses the sustained hepatic IFN-γ/TNF-α production and T cell-dependent liver injury. Int Immunopharmacol. 69, 184–193 (2019).

    CAS  PubMed  Article  Google Scholar 

  211. 211.

    Lin, C. I., Tsao, C. C. & Chuang, Y. H. IL-37 increases liver inflammation in Con A-induced hepatitis by increasing IFN-γ secretion of infiltrated NK Cells. J. Immunol. 204, 238.12 (2020).

    Google Scholar 

  212. 212.

    Fazel Modares, N. et al. IL-6 trans-signaling controls liver regeneration after partial hepatectomy. Hepatology 70, 2075–2091 (2019).

    CAS  PubMed  Article  Google Scholar 

  213. 213.

    Lokau, J. et al. Proteolytic cleavage governs interleukin-11 trans-signaling. Cell Rep. 14, 1761–1773 (2016).

    CAS  PubMed  Article  Google Scholar 

  214. 214.

    Jones, S. A., Scheller, J. & Rose-John, S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Investig. 121, 3375–3383 (2011).

    CAS  PubMed  Article  Google Scholar 

  215. 215.

    Norris, C. A. et al. Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS ONE 9, e96053 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  216. 216.

    Schmidt-Arras, D. & Rose-John, S. IL-6 pathway in the liver: from physiopathology to therapy. J. Hepatol. 64, 1403–1415 (2016).

    CAS  PubMed  Article  Google Scholar 

  217. 217.

    Gao, R. Y. et al. Hypoxia-inducible factor-2alpha reprograms liver macrophages to protect against acute liver injury through the production of interleukin-6. Hepatology 71, 2105–2117 (2020).

    CAS  PubMed  Article  Google Scholar 

  218. 218.

    Zhang, X. et al. Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. Hepatology 52, 2137–2147 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. 219.

    Miller, A. M. et al. Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice. Hepatology 54, 846–856 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  220. 220.

    Mas, E. et al. IL-6 deficiency attenuates murine diet-induced non-alcoholic steatohepatitis. PLoS One 4, e7929 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  221. 221.

    Xu, M. J. et al. Liver is the major source of elevated serum lipocalin-2 levels after bacterial infection or partial hepatectomy: a critical role for IL-6/STAT3. Hepatology 61, 692–702 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  222. 222.

    Aleksandrova, K. et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology 60, 858–871 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. 223.

    Wan, S. et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393–1404 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Bergmann, J. et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology 65, 89–103 (2017).

    CAS  PubMed  Article  Google Scholar 

  225. 225.

    Isorce, N. et al. Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus. Antivir. Res. 130, 36–45 (2016).

    CAS  PubMed  Article  Google Scholar 

  226. 226.

    Faure-Dupuy, S. et al. Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection. J. Hepatol. 71, 1086–1098 (2019).

    CAS  PubMed  Article  Google Scholar 

  227. 227.

    Lan, T., Chang, L., Wu, L. & Yuan, Y. F. IL-6 plays a crucial role in HBV infection. J. Clin. Transl. Hepatol. 3, 271–276 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  228. 228.

    Cao, Y. et al. IL-27, a cytokine, and IFN-lambda1, a type III IFN, are coordinated to regulate virus replication through type I IFN. J. Immunol. 192, 691–703 (2014).

    CAS  PubMed  Article  Google Scholar 

  229. 229.

    Negash, A. A., Olson, R. M., Griffin, S. & Gale, M. Jr Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation. PLoS Pathog. 15, e1007593 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  230. 230.

    Larrea, E. et al. Characterization of the CD40L/Oncostatin M/Oncostatin M receptor axis as an antiviral and immunostimulatory system disrupted in chronic HCV infection. J. Hepatol. 60, 482–489 (2014).

    CAS  PubMed  Article  Google Scholar 

  231. 231.

    Yu, J., Feng, Z., Tan, L., Pu, L. & Kong, L. Interleukin-11 protects mouse liver from warm ischemia/reperfusion (WI/Rp) injury. Clin. Res Hepatol. Gastroenterol. 40, 562–570 (2016).

    CAS  PubMed  Article  Google Scholar 

  232. 232.

    Widjaja, A. A. et al. Inhibiting interleukin 11 signaling reduces hepatocyte death and liver fibrosis, inflammation, and steatosis in mouse models of nonalcoholic steatohepatitis. Gastroenterology 157, 777–792 e14 (2019).

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Foglia, B. et al. Oncostatin M, A profibrogenic mediator overexpressed in non-alcoholic fatty liver disease, stimulates migration of hepatic myofibroblasts. Cells 9, 28 (2019).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  234. 234.

    Matsuda, M. et al. Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice. Hepatology 67, 296–312 (2018).

    CAS  PubMed  Article  Google Scholar 

  235. 235.

    Cui, M. X. et al. Alleviative effect of ciliary neurotrophic factor analogue on high fat-induced hepatic steatosis is partially independent of the central regulation. Clin. Exp. Pharmacol. Physiol. 44, 395–402 (2017).

    CAS  PubMed  Article  Google Scholar 

  236. 236.

    Nonogaki, K. et al. LIF and CNTF, which share the gp130 transduction system, stimulate hepatic lipid metabolism in rats. Am. J. Physiol. 271, E521–E528 (1996).

    CAS  PubMed  Google Scholar 

  237. 237.

    Guillot, A. et al. Interleukins-17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation. Hepatol. Commun. 2, 329–343 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  238. 238.

    Lopez-Yoldi, M., Moreno-Aliaga, M. J. & Bustos, M. Cardiotrophin-1: a multifaceted cytokine. Cytokine Growth Factor Rev. 26, 523–532 (2015).

    CAS  PubMed  Article  Google Scholar 

  239. 239.

    Dudakov, J. A., Hanash, A. M. & van den Brink, M. R. Interleukin-22: immunobiology and pathology. Annu Rev. Immunol. 33, 747–785 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  240. 240.

    Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22-IL-22R1 system. Nat. Rev. Drug Disco. 13, 21–38 (2014).

    CAS  Article  Google Scholar 

  241. 241.

    Rutz, S., Eidenschenk, C. & Ouyang, W. IL-22, not simply a Th17 cytokine. Immunol. Rev. 252, 116–132 (2013).

    PubMed  Article  CAS  Google Scholar 

  242. 242.

    Sabat, R. IL-10 family of cytokines. Cytokine Growth Factor Rev. 21, 315–324 (2010).

    CAS  PubMed  Article  Google Scholar 

  243. 243.

    Radaeva, S., Sun, R., Pan, H. N., Hong, F. & Gao, B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 39, 1332–1342 (2004).

    CAS  PubMed  Article  Google Scholar 

  244. 244.

    Feng, D. et al. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection. Gastroenterology 143, 188–98 e7 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  245. 245.

    Kong, X. et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56, 1150–1159 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  246. 246.

    Lejeune, D. et al. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J. Biol. Chem. 277, 33676–33682 (2002).

    CAS  PubMed  Article  Google Scholar 

  247. 247.

    Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).

    CAS  PubMed  Article  Google Scholar 

  248. 248.

    Zheng, M. et al. Therapeutic role of interleukin 22 in experimental intra-abdominal Klebsiella pneumoniae infection in mice. Infect. Immun. 84, 782–789 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  249. 249.

    Liang, S. C. et al. IL-22 induces an acute-phase response. J. Immunol. 185, 5531–5538 (2010).

    CAS  PubMed  Article  Google Scholar 

  250. 250.

    Xing, W. W. et al. Hepatoprotective effects of IL-22 on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice. Cytokine 56, 174–179 (2011).

    CAS  PubMed  Article  Google Scholar 

  251. 251.

    Park, O. et al. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology 54, 252–261 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  252. 252.

    Ashour, T. H. Therapy with interleukin-22 alleviates hepatic injury and hemostasis dysregulation in rat model of acute liver failure. Adv. Hematol. 2014, 705290 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  253. 253.

    Wahl, C., Wegenka, U. M., Leithauser, F., Schirmbeck, R. & Reimann, J. IL-22-dependent attenuation of T cell-dependent (ConA) hepatitis in herpes virus entry mediator deficiency. J. Immunol. 182, 4521–4528 (2009).

    CAS  PubMed  Article  Google Scholar 

  254. 254.

    Abe, H. et al. Aryl hydrocarbon receptor plays protective roles in ConA-induced hepatic injury by both suppressing IFN-gamma expression and inducing IL-22. Int Immunol. 26, 129–137 (2014).

    CAS  PubMed  Article  Google Scholar 

  255. 255.

    Zenewicz, L. A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  256. 256.

    Scheiermann, P. et al. Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury. Am. J. Pathol. 182, 1107–1113 (2013).

    CAS  PubMed  Article  Google Scholar 

  257. 257.

    Feng, D. et al. Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. J. Immunol. 193, 2512–2518 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  258. 258.

    Pan, H., Hong, F., Radaeva, S. & Gao, B. Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. Cell Mol. Immunol. 1, 43–49 (2004).

    CAS  PubMed  Google Scholar 

  259. 259.

    Mo, R. et al. Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury. Theranostics 8, 4170–4180 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  260. 260.

    Lai, R. et al. Protective effect of Th22 cells and intrahepatic IL-22 in drug induced hepatocellular injury. J. Hepatol. 63, 148–155 (2015).

    CAS  PubMed  Article  Google Scholar 

  261. 261.

    Ki, S. H. et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 52, 1291–1300 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  262. 262.

    Meng, F. et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765–776 e3 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  263. 263.

    Hu, B. L. et al. Interleukin-22 ameliorates liver fibrosis through miR-200a/beta-catenin. Sci. Rep. 6, 36436 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  264. 264.

    Sertorio, M. et al. IL-22 and IL-22 binding protein (IL-22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections. Hepatology 61, 1321–1331 (2015).

    CAS  PubMed  Article  Google Scholar 

  265. 265.

    Fabre, T. et al. Type 3 cytokines IL-17A and IL-22 drive TGF-beta-dependent liver fibrosis. Sci Immunol. 3 (2018).

  266. 266.

    Wu, L. Y. et al. Up-regulation of interleukin-22 mediates liver fibrosis via activating hepatic stellate cells in patients with hepatitis C. Clin. Immunol. 158, 77–87 (2015).

    CAS  PubMed  Article  Google Scholar 

  267. 267.

    Brand, S. et al. IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1019–G1028 (2007).

    CAS  PubMed  Article  Google Scholar 

  268. 268.

    Zhou, H. et al. Enhanced regeneration and hepatoprotective effects of interleukin 22 fusion protein on a predamaged liver undergoing partial hepatectomy. J. Immunol. Res. 2018, 5241526 (2018).

    PubMed  PubMed Central  Google Scholar 

  269. 269.

    Mo, R. et al. Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-related acute-on-chronic liver failure. J. Gastroenterol. Hepatol. 32, 677–686 (2017).

    CAS  PubMed  Article  Google Scholar 

  270. 270.

    Schwarzkopf, K. et al. IL-22 and IL-22-binding protein are associated with development of and mortality from acute-on-chronic liver failure. Hepatol. Commun. 3, 392–405 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  271. 271.

    Yang, L. et al. Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J. Hepatol. 53, 339–347 (2010).

    CAS  PubMed  Article  Google Scholar 

  272. 272.

    Zhang, Y. et al. A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. Gastroenterology 141, 1897–1906 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  273. 273.

    Foster, R. G., Golden-Mason, L., Rutebemberwa, A. & Rosen, H. R. Interleukin (IL)-17/IL-22-producing T cells enriched within the liver of patients with chronic hepatitis C viral (HCV) infection. Dig. Dis. Sci. 57, 381–389 (2012).

    CAS  PubMed  Article  Google Scholar 

  274. 274.

    Zhang, J. Y. et al. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology 51, 81–91 (2010).

    CAS  Article  Google Scholar 

  275. 275.

    Chang, Q. et al. Th17 cells are increased with severity of liver inflammation in patients with chronic hepatitis C. J. Gastroenterol. Hepatol. 27, 273–278 (2012).

    CAS  PubMed  Article  Google Scholar 

  276. 276.

    Zhao, J. et al. Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology 59, 1331–1342 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  277. 277.

    Dambacher, J. et al. The role of interleukin-22 in hepatitis C virus infection. Cytokine 41, 209–216 (2008).

    CAS  PubMed  Article  Google Scholar 

  278. 278.

    Jiang, R. et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 54, 900–909 (2011).

    CAS  PubMed  Article  Google Scholar 

  279. 279.

    Shi, J. et al. Interleukin 22 is related to development and poor prognosis of hepatocellular carcinoma. Clin. Res. Hepatol. Gastroenterol. (2020). in press, https://doi.org/10.1016/j.clinre.2020.01.009.

  280. 280.

    Waidmann, O. et al. Interleukin-22 serum levels are a negative prognostic indicator in patients with hepatocellular carcinoma. Hepatology 59, 1207 (2014).

    CAS  PubMed  Article  Google Scholar 

  281. 281.

    Tang, K. Y. et al. Safety, pharmacokinetics, and biomarkers of F-652, a recombinant human interleukin-22 dimer, in healthy subjects. Cell Mol. Immunol. 16, 473–482 (2019).

    CAS  PubMed  Article  Google Scholar 

  282. 282.

    Rothenberg, M. E. et al. Randomized Phase I healthy volunteer study of UTTR1147A (IL-22Fc): a potential therapy for epithelial injury. Clin. Pharmacol. Ther. 105, 177–189 (2019).

    CAS  PubMed  Article  Google Scholar 

  283. 283.

    Arab, J. P. et al. An open-label, dose-escalation study to assess the safety and efficacy of IL-22 agonist F-652 in patients with alcohol-associated hepatitis. Hepatology 72, 441–453 (2019).

    Article  CAS  Google Scholar 

  284. 284.

    Xiang, X., Hwang, S., Feng, D., Shah, V. H. & Gao, B. Interleukin-22 in alcoholic hepatitis and beyond. Hepatol. Int 14, 667–676 (2020).

    PubMed  Article  Google Scholar 

  285. 285.

    Wolk, K., Kunz, S., Asadullah, K. & Sabat, R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J. Immunol. 168, 5397–5402 (2002).

    CAS  PubMed  Article  Google Scholar 

  286. 286.

    Wegenka, U. M., Dikopoulos, N., Reimann, J., Adler, G. & Wahl, C. The murine liver is a potential target organ for IL-19, IL-20 and IL-24: Type I interferons and LPS regulate the expression of IL-20R2. J. Hepatol. 46, 257–265 (2007).

    CAS  PubMed  Article  Google Scholar 

  287. 287.

    Hsu, Y. H. et al. Interleukin-19 mediates tissue damage in murine ischemic acute kidney injury. PLoS ONE 8, e56028 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  288. 288.

    Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).

    CAS  PubMed  Article  Google Scholar 

  289. 289.

    Caparros, E. & Frances, R. The interleukin-20 cytokine family in liver disease. Front. Immunol. 9, 1155 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  290. 290.

    Chiu, Y. S., Wei, C. C., Lin, Y. J., Hsu, Y. H. & Chang, M. S. IL-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology 60, 1003–1014 (2014).

    CAS  PubMed  Article  Google Scholar 

  291. 291.

    Ding, W. Z. et al. Anti-IL-20 monoclonal antibody suppresses hepatocellular carcinoma progression. Oncol. Lett. 16, 6156–6162 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  292. 292.

    Chiu, Y. S. et al. Anti-IL-20 monoclonal antibody inhibited tumor growth in hepatocellular carcinoma. Sci. Rep. 7, 17609 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  293. 293.

    Menezes, M. E. et al. MDA-7/IL-24: multifunctional cancer killing cytokine. Adv. Exp. Med Biol. 818, 127–153 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  294. 294.

    Chen, W. Y. et al. IL-24 inhibits the growth of hepatoma cells in vivo. Genes Immun. 6, 493–499 (2005).

    CAS  PubMed  Article  Google Scholar 

  295. 295.

    Wang, C. J. et al. Interferon-alpha enhances antitumor activities of oncolytic adenovirus-mediated IL-24 expression in hepatocellular carcinoma. Mol. Cancer 11, 31 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  296. 296.

    Liu, X. et al. Gene-viro-therapy targeting liver cancer by a dual-regulated oncolytic adenoviral vector harboring IL-24 and TRAIL. Cancer Gene Ther. 19, 49–57 (2012).

    PubMed  Article  CAS  Google Scholar 

  297. 297.

    Tong, A. W. et al. Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol. Ther. 11, 160–172 (2005).

    CAS  PubMed  Article  Google Scholar 

  298. 298.

    Cunningham, C. C. et al. Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma: a phase I study. Mol. Ther. 11, 149–159 (2005).

    CAS  PubMed  Article  Google Scholar 

  299. 299.

    Fisher, P. B. et al. mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene: from the laboratory into the clinic. Cancer Biol. Ther. 2, S23–S37 (2003).

    CAS  PubMed  Article  Google Scholar 

  300. 300.

    Wang, J. et al. Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver. Cell Death Dis. 11, 17 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  301. 301.

    Knappe, A., Hor, S., Wittmann, S. & Fickenscher, H. Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J. Virol. 74, 3881–3887 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  302. 302.

    Hor, S. et al. The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains. J. Biol. Chem. 279, 33343–33351 (2004).

    PubMed  Article  CAS  Google Scholar 

  303. 303.

    Miot, C. et al. IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells. Gut 64, 1466–1475 (2015).

    CAS  PubMed  Article  Google Scholar 

  304. 304.

    Xi, Z. F. et al. Expression of IL-26 predicts prognosis of patients with hepatocellular carcinoma after surgical resection. Hepatobiliary Pancreat. Dis. Int 18, 242–248 (2019).

    PubMed  Article  Google Scholar 

  305. 305.

    Hu, Z. et al. miRNA-132-3p inhibits osteoblast differentiation by targeting Ep300 in simulated microgravity. Sci. Rep. 5, 18655 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  306. 306.

    Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).

    CAS  PubMed  Article  Google Scholar 

  307. 307.

    Arshad, M. I. et al. TRAIL but not FasL and TNFalpha, regulates IL-33 expression in murine hepatocytes during acute hepatitis. Hepatology 56, 2353–2362 (2012).

    CAS  PubMed  Article  Google Scholar 

  308. 308.

    von Freeden-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).

    Article  Google Scholar 

  309. 309.

    Sawa, Y. et al. Hepatic interleukin-7 expression regulates T cell responses. Immunity 30, 447–457 (2009).

    CAS  PubMed  Article  Google Scholar 

  310. 310.

    Liang, B. et al. Role of hepatocyte-derived IL-7 in maintenance of intrahepatic NKT cells and T cells and development of B cells in fetal liver. J. Immunol. 189, 4444–4450 (2012).

    CAS  PubMed  Article  Google Scholar 

  311. 311.

    Nishina, T. et al. Interleukin-11 links oxidative stress and compensatory proliferation. Sci. Signal 5, ra5 (2012).

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

The current review covers a very broad topic, and the authors apologize to the colleagues whose work was not mentioned or cited in this paper because of space constraints and the limited number of references that are allowed. The work from the authors’ laboratories described in this review article was supported by the intramural program of the NIAAA (Bin Gao), U01 AA022614, and R01 DK099205 (Tatiana Kisseleva) and AA011576 and AA017729 (Gyongyi Szabo).

Author information

Affiliations

Authors

Contributions

Y.H. and S.H. share first authorship. Y.H. wrote the sections on Th1 and IL-20 family cytokines and hepatocyte-derived cytokines; S.H. wrote the sections on Th2 and Th9 cytokines; Y.A.A. and F.L. wrote the section on IL-6 family cytokines; D.F. wrote the section on IL-22 cytokine; N.L. and T.K. wrote the section on IL-17 family cytokines; M.R. and G.S. wrote the section on IL-1 family cytokines; and B.G. initiated and supervised the paper writing process and edited the paper. Y.A.A. was a participant in the NIH Graduate Partnerships Program and a graduate student at the Université Paris-Est, France and is affiliated with the Université Paris-Est and the NIH Graduate Partnerships Program.

Corresponding author

Correspondence to Bin Gao.

Ethics declarations

Competing interests

G.S. consults for Allergan, Alnylam, Arrow, Durcect Corporation, Generon, Glympse Bio, Terra Firma, Quest Diagnostics, Pandion Therapeutics, Surrozen, and Zomagen. She has received grants from Gilead, Genfit, Intercept, Novartis, SignaBlok, and Shire. She holds intellectual property rights with Up to Date. The other coauthors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

He, Y., Hwang, S., Ahmed, Y.A. et al. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol (2020). https://doi.org/10.1038/s41423-020-00580-w

Download citation

Keywords

  • T helper; ALD
  • NAFLD
  • Fibrosis
  • Inflammation

Search