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New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology

Abstract

IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease. A newly engineered gp130 cytokine, IC7Fc, has shown promising preclinical results for the treatment of type 2 diabetes, obesity and liver steatosis. Moreover, drugs that modulate gp130 signalling have shown promise in refractory inflammatory bowel disease in clinical trials. A deeper understanding of the main roles of the IL-6 family of cytokines during homeostatic and pathological conditions, their signalling pathways, sources of production and target cells will be crucial to the development of improved treatments. Here, we review the current state of the role of these cytokines in hepatology and gastroenterology and discuss the progress achieved in translating therapeutics targeting gp130 signalling into clinical practice.

Key points

  • Evidence from animal and human studies supports the role of IL-6 family cytokines in regulating metabolic, hepatic and gastroenterology homeostasis.

  • Activation of gp130 signalling can be detrimental in some contexts and contribute to metabolic, liver and gastrointestinal disorders such as obesity, chronic liver damage, inflammatory bowel disease (IBD) and cancer.

  • Further insights into the involvement of IL-6 family cytokines in homeostasis and the pathophysiology of different disorders are required to develop treatments with adequate risk–benefit profiles.

  • Some therapies targeting gp130 signalling (for example, spg130Fc and JAK inhibitors) are promising novel disease-modifying biological treatments for refractory IBD.

  • Preclinical studies have shown that engineered IL-6 family cytokines such as IC7Fc are promising for the treatment of type 2 diabetes, obesity and liver steatosis.

  • New approaches such as gp130–cytokine fusion proteins, soluble antagonist receptors and more selective or tissue-specific inhibitors of gp130 signalling might improve the effectiveness and safety profile of this class of therapy.

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Fig. 1: IL-6 family signalling complex.
Fig. 2: Modes of IL-6 and IL-11 signalling.
Fig. 3: Signalling of other members of the IL-6 family cytokines.
Fig. 4: Intracellular signalling mechanisms linked to gp130.
Fig. 5: gp130 cytokines involved in the pathophysiology of human metabolic, liver and gastrointestinal disorders.
Fig. 6: Therapeutic interventions that target gp130 signalling.
Fig. 7: Adverse effects of anti-IL-6 drugs and anti-JAK inhibitors.

References

  1. 1.

    Rose-John, S., Scheller, J. & Schaper, F. “Family reunion”–A structured view on the composition of the receptor complexes of interleukin-6-type and interleukin-12-type cytokines. Cytokine Growth Factor. Rev. 26, 471–474 (2015).

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Johnson, D. E., O’Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  3. 3.

    Hunter, C. A. & Jones, S. A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 16, 448–457 (2015).

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Garbers, C., Heink, S., Korn, T. & Rose-John, S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat. Rev. Drug Discov. 17, 395–412 (2018).

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Findeisen, M. et al. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature 574, 63–68 (2019).

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Mitsuyama, K. et al. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Res. 27, 3749–3756 (2007).

    CAS  PubMed  Google Scholar 

  7. 7.

    Rose-John, S. Cytokines come of age. Biochim. Biophys. Acta 1592, 213–214 (2002).

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Wang, X., Lupardus, P., Laporte, S. L. & Garcia, K. C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27, 29–60 (2009).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  9. 9.

    Wilmes, S. et al. Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science 367, 643–652 (2020).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  10. 10.

    Garbers, C. et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor. Rev. 23, 85–97 (2012).

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Grötzinger, J., Kurapkat, G., Wollmer, A., Kalai, M. & Rose-John, S. The family of the IL-6-type cytokines: specificity and promiscuity of the receptor complexes. Proteins 27, 96–109 (1997).

    Article  PubMed  Google Scholar 

  12. 12.

    Wilkinson, A. N. et al. Granulocytes are unresponsive to IL-6 due to an absence of gp130. J. Immunol. 200, 3547–3555 (2018).

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Jones, S. A. & Jenkins, B. J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat. Rev. Immunol. 18, 773–789 (2018).

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Lokau, J. & Garbers, C. Biological functions and therapeutic opportunities of soluble cytokine receptors. Cytokine Growth Factor Rev. 55, 94–108 (2020).

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Riethmueller, S. et al. Proteolytic origin of the soluble human IL-6R in vivo and a decisive role of N-glycosylation. PLoS Biol. 15, e2000080 (2017).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  16. 16.

    Müllberg, J. et al. The soluble interleukin-6 receptor is generated by shedding. Eur. J. Immunol. 23, 473–480 (1993).

    Article  PubMed  Google Scholar 

  17. 17.

    Heink, S. et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T(H)17 cells. Nat. Immunol. 18, 74–85 (2017).

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Garbers, C. & Scheller, J. Interleukin-6 and interleukin-11: same same but different. Biol. Chem. 394, 1145–1161 (2013).

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Putoczki, T. & Ernst, M. More than a sidekick: the IL-6 family cytokine IL-11 links inflammation to cancer. J. Leukoc. Biol. 88, 1109–1117 (2010).

    CAS  Article  PubMed  Google Scholar 

  20. 20.

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

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Sun, B. B. et al. Genomic atlas of the human plasma proteome. Nature 558, 73–79 (2018).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. 22.

    Lamertz, L. et al. Soluble gp130 prevents interleukin-6 and interleukin-11 cluster signaling but not intracellular autocrine responses. Sci. Signal 11, eaar7388 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1–20 (2003).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  24. 24.

    Schaper, F. & Rose-John, S. Interleukin-6: biology, signaling and strategies of blockade. Cytokine Growth Factor. Rev. 26, 475–487 (2015).

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Bastard, J. P. et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J. Clin. Endocrinol. Metab. 85, 3338–3342 (2000).

    CAS  PubMed  Google Scholar 

  26. 26.

    Steensberg, A. et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. 529, 237–242 (2000).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  27. 27.

    Wojtaszewski, J. F. & Richter, E. A. Effects of acute exercise and training on insulin action and sensitivity: focus on molecular mechanisms in muscle. Essays Biochem. 42, 31–46 (2006).

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Wallenius, V. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 8, 75–79 (2002).

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Matthews, V. B. et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53, 2431–2441 (2010).

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Sadagurski, M. et al. Human IL6 enhances leptin action in mice. Diabetologia 53, 525–535 (2010).

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. 32.

    Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-βB. Nat. Med. 11, 183–190 (2005).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  33. 33.

    Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  34. 34.

    Ellingsgaard, H. et al. GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study. Diabetologia 63, 362–373 (2020).

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Han, M. S. et al. Regulation of adipose tissue inflammation by interleukin 6. Proc. Natl Acad. Sci. USA 117, 2751–2760 (2020).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. 36.

    Perry, R. J. et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160, 745–758 (2015).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. 37.

    Yamaguchi, K. et al. Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high-fat diet fed mice. Liver Int. 35, 550–561 (2015).

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Yamaguchi, K. et al. Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Lab. Invest. 90, 1169–1178 (2010).

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Wunderlich, F. T. et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 12, 237–249 (2010).

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423–430 (2014).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  41. 41.

    Timper, K. et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep. 19, 267–280 (2017).

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Masu, Y. et al. Disruption of the CNTF gene results in motor neuron degeneration. Nature 365, 27–32 (1993).

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Pascual-Gamarra, J. M. et al. Association between CNTF polymorphisms and adiposity markers in European adolescents. J. Pediatr. 219, 23–30.e1 (2020).

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Watt, M. J. et al. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat. Med. 12, 541–548 (2006).

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Zvonic, S., Cornelius, P., Stewart, W. C., Mynatt, R. L. & Stephens, J. M. The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. J. Biol. Chem. 278, 2228–2235 (2003).

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Perugini, J. et al. Biological effects of ciliary neurotrophic factor on hMADS adipocytes. Front. Endocrinol. 10, 768 (2019).

    Article  Google Scholar 

  47. 47.

    Sleeman, M. W. et al. Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice. Proc. Natl Acad. Sci. USA 100, 14297–14302 (2003).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  48. 48.

    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  Article  PubMed  Google Scholar 

  49. 49.

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

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Castaño, D. et al. Cardiotrophin-1 eliminates hepatic steatosis in obese mice by mechanisms involving AMPK activation. J. Hepatol. 60, 1017–1025 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Carneros, D. et al. Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization. FASEB J. 33, 7578–7587 (2019).

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Lutz, S. Z. et al. Common genetic variation in the human CTF1 locus, encoding cardiotrophin-1, determines insulin sensitivity. PLoS ONE 9, e100391 (2014).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  53. 53.

    Rosado-Olivieri, E. A., Aigha, I. I., Kenty, J. H. & Melton, D. A. Identification of a LIF-responsive, replication-competent subpopulation of human β cells. Cell Metab. 31, 327–338.e6 (2020).

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Stephens, J., Ravussin, E. & White, U. The expression of adipose tissue-derived cardiotrophin-1 in humans with obesity. Biology 8, 24 (2019).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  55. 55.

    Brandt, N. et al. Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 309, E142–E153 (2015).

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Broholm, C. et al. Deficient leukemia inhibitory factor signaling in muscle precursor cells from patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 303, E283–E292 (2012).

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505–1513 (2018).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  58. 58.

    Tanaka, M. et al. Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit. Blood 93, 804–815 (1999).

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Luo, P. et al. Hepatic oncostatin M receptor β regulates obesity-induced steatosis and insulin resistance. Am. J. Pathol. 186, 1278–1292 (2016).

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Henkel, J. et al. Oncostatin M produced in Kupffer cells in response to PGE2: possible contributor to hepatic insulin resistance and steatosis. Lab. Invest. 91, 1107–1117 (2011).

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Komori, T., Tanaka, M., Senba, E., Miyajima, A. & Morikawa, Y. Deficiency of oncostatin M receptor β (OSMRβ) exacerbates high-fat diet-induced obesity and related metabolic disorders in mice. J. Biol. Chem. 289, 13821–13837 (2014).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  62. 62.

    Baumann, H. & Gauldie, J. The acute phase response. Immunol. Today 15, 74–80 (1994).

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Espat, N. J. et al. Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response. Am. J. Physiol. 271, R185–R190 (1996).

    CAS  PubMed  Google Scholar 

  64. 64.

    Baumann, H. & Schendel, P. Interleukin-11 regulates the hepatic expression of the same plasma protein genes as interleukin-6. J. Biol. Chem. 266, 20424–20427 (1991).

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Peters, M., Roeb, E., Pennica, D., Meyer zum Büschenfelde, K. H. & Rose-John, S. A new hepatocyte stimulating factor: cardiotrophin-1 (CT-1). FEBS Lett. 372, 177–180 (1995).

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Schooltink, H., Stoyan, T., Roeb, E., Heinrich, P. C. & Rose-John, S. Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes. FEBS Lett. 314, 280–284 (1992).

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Senaldi, G. et al. Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family. Proc. Natl Acad. Sci.USA 96, 11458–11463 (1999).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  68. 68.

    Dittrich, F., Thoenen, H. & Sendtner, M. Ciliary neurotrophic factor: pharmacokinetics and acute-phase response in rat. Ann. Neurol. 35, 151–163 (1994).

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Geiger, T. et al. Induction of rat acute-phase proteins by interleukin 6 in vivo. Eur. J. Immunol. 18, 717–721 (1988).

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Metcalf, D., Nicola, N. A. & Gearing, D. P. Effects of injected leukemia inhibitory factor on hematopoietic and other tissues in mice. Blood 76, 50–56 (1990).

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Wallace, P. M. et al. In vivo properties of oncostatin M. Ann. N. Y. Acad. Sci. 762, 42–54 (1995).

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Yonemura, Y., Kawakita, M., Masuda, T., Fujimoto, K. & Takatsuki, K. Effect of recombinant human interleukin-11 on rat megakaryopoiesis and thrombopoiesis in vivo: comparative study with interleukin-6. Br. J. Haematol. 84, 16–23 (1993).

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Matthews, V. B. et al. Oncostatin M induces an acute phase response but does not modulate the growth or maturation-status of liver progenitor (oval) cells in culture. Exp. Cell Res. 306, 252–263 (2005).

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Dierssen, U. et al. Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration. J. Biol. Chem. 283, 9886–9895 (2008).

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Alonzi, T. et al. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver. Mol. Cell Biol. 21, 1621–1632 (2001).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  76. 76.

    Kopf, M. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368, 339–342 (1994).

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    McFarland-Mancini, M. M. et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J. Immunol. 184, 7219–7228 (2010).

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Weber, M. A. et al. Endogenous leukemia inhibitory factor attenuates endotoxin response. Lab. Invest. 85, 276–284 (2005).

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Wallace, P. M. et al. Regulation of inflammatory responses by oncostatin M. J. Immunol. 162, 5547–5555 (1999).

    CAS  PubMed  Google Scholar 

  80. 80.

    Puel, A. et al. Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J. Immunol. 180, 647–654 (2008).

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Nanki, T. et al. Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections. Ann. Rheum. Dis. 72, 1100–1102 (2013).

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Bloomfield, M. et al. Anti-IL6 autoantibodies in an infant with CRP-less septic shock. Front. Immunol. 10, 2629 (2019).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  83. 83.

    Shafran, I. H., Alasti, F., Smolen, J. S. & Aletaha, D. Implication of baseline levels and early changes of C-reactive protein for subsequent clinical outcomes of patients with rheumatoid arthritis treated with tocilizumab. Ann. Rheum. Dis. 79, 874–882 (2020).

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Lee, J. Y. et al. Serum amyloid A proteins induce pathogenic Th17 cells and promote inflammatory disease. Cell 180, 79–91.e16 (2020).

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Michalopoulos, G. K. & DeFrances, M. C. Liver regeneration. Science 276, 60–66 (1997).

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Michalopoulos, G. K. Liver regeneration. J. Cell Physiol. 213, 286–300 (2007).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  87. 87.

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

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Drucker, C., Gewiese, J., Malchow, S., Scheller, J. & Rose-John, S. Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration. J. Autoimmun. 34, 29–37 (2010).

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Haga, S. et al. Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice. J. Hepatol. 43, 799–807 (2005).

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Riehle, K. J. et al. Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3. J. Exp. Med. 205, 91–103 (2008).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  91. 91.

    Cressman, D. E. et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274, 1379–1383 (1996).

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Blindenbacher, A. et al. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology 38, 674–682 (2003).

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Fulop, A. K. et al. Hepatic regeneration induces transient acute phase reaction: systemic elevation of acute phase reactants and soluble cytokine receptors. Cell Biol. Int. 25, 585–592 (2001).

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Peters, M. et al. Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice. J. Exp. Med. 185, 755–766 (1997).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  95. 95.

    Maione, D. et al. Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver. EMBO J. 17, 5588–5597 (1998).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  96. 96.

    Nechemia-Arbely, Y. et al. Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation. J. Hepatol. 54, 922–929 (2011).

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Nakamura, K., Nonaka, H., Saito, H., Tanaka, M. & Miyajima, A. Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice. Hepatology 39, 635–644 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. 98.

    Okaya, A. et al. Oncostatin M inhibits proliferation of rat oval cells, OC15-5, inducing differentiation into hepatocytes. Am. J. Pathol. 166, 709–719 (2005).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  99. 99.

    Hamada, T. et al. Oncostatin M gene therapy attenuates liver damage induced by dimethylnitrosamine in rats. Am. J. Pathol. 171, 872–881 (2007).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  100. 100.

    Yang, Z. F. et al. Cardiotrophin-1 enhances regeneration of cirrhotic liver remnant after hepatectomy through promotion of angiogenesis and cell proliferation. Liver Int. 28, 622–631 (2008).

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Omori, N. et al. Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. Lab. Invest. 75, 15–24 (1996).

    CAS  PubMed  Google Scholar 

  102. 102.

    Rosenberg, D., Ilic, Z., Yin, L. & Sell, S. Proliferation of hepatic lineage cells of normal C57BL and interleukin-6 knockout mice after cocaine-induced periportal injury. Hepatology 31, 948–955 (2000).

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Gajalakshmi, P. et al. Interleukin-6 secreted by bipotential murine oval liver stem cells induces apoptosis of activated hepatic stellate cells by activating NF-κB-inducible nitric oxide synthase signaling. Biochem. Cell Biol. 95, 263–272 (2017).

    CAS  Article  PubMed  Google Scholar 

  104. 104.

    Fausto, N. & Campbell, J. S. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech. Dev. 120, 117–130 (2003).

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Tirnitz-Parker, J. E. E., Forbes, S. J., Olynyk, J. K. & Ramm, G. A. Cellular plasticity in liver regeneration: spotlight on cholangiocytes. Hepatology 69, 2286–2289 (2019).

    Article  PubMed  Google Scholar 

  106. 106.

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

    Article  CAS  PubMed  Google Scholar 

  107. 107.

    Wahl, A. F. & Wallace, P. M. Oncostatin M in the anti-inflammatory response. Ann. Rheum. Dis. 60, iii75–iii80 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  108. 108.

    Zhu, C. et al. Hepatitis B virus enhances interleukin-27 expression both in vivo and in vitro. Clin. Immunol. 131, 92–97 (2009).

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Katz, A., Chebath, J., Friedman, J. & Revel, M. Increased sensitivity of IL-6-deficient mice to carbon tetrachloride hepatotoxicity and protection with an IL-6 receptor-IL-6 chimera. Cytokines Cell Mol. Ther. 4, 221–227 (1998).

    CAS  PubMed  Google Scholar 

  110. 110.

    Klein, C. et al. The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. J. Clin. Invest. 115, 860–869 (2005).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  111. 111.

    Camargo, C. A. Jr., Madden, J. F., Gao, W., Selvan, R. S. & Clavien, P. A. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology 26, 1513–1520 (1997).

    CAS  Article  PubMed  Google Scholar 

  112. 112.

    Hoge, J. et al. IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling. J. Immunol. 190, 703–711 (2013).

    CAS  Article  PubMed  Google Scholar 

  113. 113.

    Jostock, T. et al. Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur. J. Biochem. 268, 160–167 (2001).

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Barkhausen, T. et al. Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit. Care Med. 39, 1407–1413 (2011).

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Li, S. Q., Zhu, S., Han, H. M., Lu, H. J. & Meng, H. Y. IL-6 trans-signaling plays important protective roles in acute liver injury induced by acetaminophen in mice. J. Biochem. Mol. Toxicol. 29, 288–297 (2015).

    CAS  Article  PubMed  Google Scholar 

  116. 116.

    Gewiese-Rabsch, J., Drucker, C., Malchow, S., Scheller, J. & Rose-John, S. Role of IL-6 trans-signaling in CCl4 induced liver damage. Biochim. Biophys. Acta 1802, 1054–1061 (2010).

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Zhao, J., Qi, Y. F. & Yu, Y. R. STAT3: a key regulator in liver fibrosis. Ann. Hepatol. 21, 100224 (2021).

    CAS  Article  PubMed  Google Scholar 

  118. 118.

    Maeshima, K. et al. A protective role of interleukin 11 on hepatic injury in acute endotoxemia. Shock 21, 134–138 (2004).

    CAS  Article  PubMed  Google Scholar 

  119. 119.

    Kawakami, T. et al. Highly liver-specific heme oxygenase-1 induction by interleukin-11 prevents carbon tetrachloride-induced hepatotoxicity. Int. J. Mol. Med. 18, 537–546 (2006).

    CAS  PubMed  Google Scholar 

  120. 120.

    Widjaja, A. A., Chothani, S. P. & Cook, S. A. Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy. Hum. Vaccin. Immunother. 16, 2357–2362 (2020).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  121. 121.

    Richards, C. D. The enigmatic cytokine oncostatin M and roles in disease. ISRN Inflamm. 2013, 512103 (2013).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  122. 122.

    Jones, G. W., Hill, D. G., Cardus, A. & Jones, S. A. IL-27: a double agent in the IL-6 family. Clin. Exp. Immunol. 193, 37–46 (2018).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  123. 123.

    Iñiguez, M. et al. Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning. J. Exp. Med. 203, 2809–2815 (2006).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  124. 124.

    Tuñon, M. J. et al. Cardiotrophin-1 promotes a high survival rate in rabbits with lethal fulminant hepatitis of viral origin. J. Virol. 85, 13124–13132 (2011).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  125. 125.

    Sheng, T. et al. The relationship between serum interleukin-6 and the recurrence of hepatitis B virus related hepatocellular carcinoma after curative resection. Medicine 94, e941 (2015).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  126. 126.

    Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).

    CAS  Article  Google Scholar 

  127. 127.

    Bosch, F. X., Ribes, J., Diaz, M. & Cleries, R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 127, S5–S16 (2004).

    Article  PubMed  Google Scholar 

  128. 128.

    Giannitrapani, L. et al. Circulating IL-6 and sIL-6R in patients with hepatocellular carcinoma. Ann. N. Y. Acad. Sci. 963, 46–52 (2002).

    CAS  Article  PubMed  Google Scholar 

  129. 129.

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

    CAS  Article  PubMed  Google Scholar 

  130. 130.

    Rose-John, S. The soluble interleukin 6 receptor: advanced therapeutic options in inflammation. Clin. Pharmacol. Ther. 102, 591–598 (2017).

    CAS  Article  PubMed  Google Scholar 

  131. 131.

    Xiang, Z. L., Zeng, Z. C., Fan, J., Tang, Z. Y. & Zeng, H. Y. Expression of connective tissue growth factor and interleukin-11 in intratumoral tissue is associated with poor survival after curative resection of hepatocellular carcinoma. Mol. Biol. Rep. 39, 6001–6006 (2012).

    CAS  Article  PubMed  Google Scholar 

  132. 132.

    Zheng, H. et al. TMED3 promotes hepatocellular carcinoma progression via IL-11/STAT3 signaling. Sci. Rep. 6, 37070 (2016).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  133. 133.

    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  Article  PubMed  Google Scholar 

  134. 134.

    Hisaka, T. et al. Expression of leukemia inhibitory factor (LIF) and its receptor gp190 in human liver and in cultured human liver myofibroblasts. Cloning of new isoforms of LIF mRNA. Comp. Hepatol. 3, 10 (2004).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  135. 135.

    Santos, G. C. et al. Leukemia inhibitory factor (LIF) overexpression increases the angiogenic potential of bone marrow mesenchymal stem/stromal cells. Front. Cell Dev. Biol. 8, 778 (2020).

    PubMed Central  PubMed  Article  Google Scholar 

  136. 136.

    Ferrara, N., Winer, J. & Henzel, W. J. Pituitary follicular cells secrete an inhibitor of aortic endothelial cell growth: identification as leukemia inhibitory factor. Proc. Natl Acad. Sci. USA 89, 698–702 (1992).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  137. 137.

    Shi, Y. et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569, 131–135 (2019).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  138. 138.

    Levy, M. T., Trojanowska, M. & Reuben, A. Oncostatin M: a cytokine upregulated in human cirrhosis, increases collagen production by human hepatic stellate cells. J. Hepatol. 32, 218–226 (2000).

    CAS  Article  PubMed  Google Scholar 

  139. 139.

    Rebouissou, S. et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457, 200–204 (2009).

    CAS  Article  Google Scholar 

  140. 140.

    Pilati, C. et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J. Exp. Med. 208, 1359–1366 (2011).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  141. 141.

    Poussin, K. et al. Biochemical and functional analyses of gp130 mutants unveil JAK1 as a novel therapeutic target in human inflammatory hepatocellular adenoma. Oncoimmunology 2, e27090 (2013).

    Article  PubMed  Google Scholar 

  142. 142.

    Okamura, Y. et al. Leukemia inhibitory factor receptor (LIFR) is detected as a novel suppressor gene of hepatocellular carcinoma using double-combination array. Cancer Lett. 289, 170–177 (2010).

    CAS  Article  PubMed  Google Scholar 

  143. 143.

    Luo, Q. et al. Leukemia inhibitory factor receptor is a novel immunomarker in distinction of well-differentiated HCC from dysplastic nodules. Oncotarget 6, 6989–6999 (2015).

    PubMed Central  PubMed  Article  Google Scholar 

  144. 144.

    Ernst, M., Thiem, S., Nguyen, P. M., Eissmann, M. & Putoczki, T. L. Epithelial gp130/Stat3 functions: an intestinal signaling node in health and disease. Semin. Immunol. 26, 29–37 (2014).

    CAS  Article  PubMed  Google Scholar 

  145. 145.

    Harris, P. R. et al. Recombinant Helicobacter pylori urease activates primary mucosal macrophages. J. Infect. Dis. 178, 1516–1520 (1998).

    CAS  Article  PubMed  Google Scholar 

  146. 146.

    Sobala, G. M. et al. Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations. Gut 32, 1415–1418 (1991).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  147. 147.

    Crabtree, J. E. Immune and inflammatory responses to Helicobacter pylori infection. Scand. J. Gastroenterol. Suppl. 215, 3–10 (1996).

    CAS  Article  PubMed  Google Scholar 

  148. 148.

    Furukawa, K., Takahashi, T., Arai, F., Matsushima, K. & Asakura, H. Enhanced mucosal expression of interleukin-6 mRNA but not of interleukin-8 mRNA at the margin of gastric ulcer in Helicobacter pylori-positive gastritis. J. Gastroenterol. 33, 625–633 (1998).

    CAS  Article  PubMed  Google Scholar 

  149. 149.

    Nishida, T. et al. Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1041–G1050 (2006).

    CAS  Article  PubMed  Google Scholar 

  150. 150.

    Pradeepkumar Singh, L., Kundu, P., Ganguly, K., Mishra, A. & Swarnakar, S. Novel role of famotidine in downregulation of matrix metalloproteinase-9 during protection of ethanol-induced acute gastric ulcer. Free Radic. Biol. Med. 43, 289–299 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. 151.

    Wen, C. Y. et al. Mechanism of the antiulcerogenic effect of IL-11 on acetic acid-induced gastric ulcer in rats. Life Sci. 70, 2997–3005 (2002).

    CAS  Article  PubMed  Google Scholar 

  152. 152.

    Judd, L. M., Ulaganathan, M., Howlett, M. & Giraud, A. S. Cytokine signalling by gp130 regulates gastric mucosal healing after ulceration and, indirectly, antral tumour progression. J. Pathol. 217, 552–562 (2009).

    CAS  Article  PubMed  Google Scholar 

  153. 153.

    Gallucci, R. M. et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 14, 2525–2531 (2000).

    CAS  Article  PubMed  Google Scholar 

  154. 154.

    Ernst, M. et al. Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J. Exp. Med. 194, 189–203 (2001).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  155. 155.

    de Souza, H. S. P., Fiocchi, C. & Iliopoulos, D. The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat. Rev. Gastroenterol. Hepatol. 14, 739–749 (2017).

    Article  PubMed  Google Scholar 

  156. 156.

    Hosokawa, T. et al. Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease. J. Gastroenterol. Hepatol. 14, 987–996 (1999).

    CAS  Article  PubMed  Google Scholar 

  157. 157.

    Ganter, U., Arcone, R., Toniatti, C., Morrone, G. & Ciliberto, G. Dual control of C-reactive protein gene expression by interleukin-1 and interleukin-6. EMBO J. 8, 3773–3779 (1989).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  158. 158.

    Reinecker, H. C. et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1β by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin. Exp. Immunol. 94, 174–181 (1993).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  159. 159.

    Lovato, P. et al. Constitutive STAT3 activation in intestinal T cells from patients with Crohn’s disease. J. Biol. Chem. 278, 16777–16781 (2003).

    CAS  Article  PubMed  Google Scholar 

  160. 160.

    Mudter, J. et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am. J. Gastroenterol. 100, 64–72 (2005).

    CAS  Article  PubMed  Google Scholar 

  161. 161.

    Li, Y. et al. Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut 59, 227–235 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. 162.

    Mitsuyama, K. et al. Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut 36, 45–49 (1995).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  163. 163.

    Gustot, T. et al. Profile of soluble cytokine receptors in Crohn’s disease. Gut 54, 488–495 (2005).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  164. 164.

    Yamamoto, M., Yoshizaki, K., Kishimoto, T. & Ito, H. IL-6 is required for the development of Th1 cell-mediated murine colitis. J. Immunol. 164, 4878–4882 (2000).

    CAS  Article  PubMed  Google Scholar 

  165. 165.

    Parisinos, C. A. et al. Variation in interleukin 6 receptor gene associates with risk of Crohn’s disease and ulcerative colitis. Gastroenterology 155, 303–306.e2 (2018).

    CAS  Article  PubMed  Google Scholar 

  166. 166.

    Garbers, C. et al. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim. Biophys. Acta 1842, 1485–1494 (2014).

    CAS  Article  PubMed  Google Scholar 

  167. 167.

    Scheller, J. & Rose-John, S. The interleukin 6 pathway and atherosclerosis. Lancet 380, 338 (2012).

    Article  PubMed  Google Scholar 

  168. 168.

    Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  169. 169.

    Qiu, B. S., Pfeiffer, C. J. & Keith, J. C. Jr. Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats. Dig. Dis. Sci. 41, 1625–1630 (1996).

    CAS  Article  PubMed  Google Scholar 

  170. 170.

    Keith, J. C. Jr., Albert, L., Sonis, S. T., Pfeiffer, C. J. & Schaub, R. G. IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cell 12, 79–89; discussion 89-90 (1994).

    Google Scholar 

  171. 171.

    Greenwood-Van Meerveld, B., Venkova, K. & Keith, J. C. Jr. Recombinant human interleukin-11 restores smooth muscle function in the jejunum and colon of human leukocyte antigen-B27 rats with intestinal inflammation. J. Pharmacol. Exp. Ther. 299, 58–66 (2001).

    CAS  PubMed  Google Scholar 

  172. 172.

    Gibson, D. L. et al. Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling. Gastroenterology 139, 1277–1288 (2010).

    CAS  Article  PubMed  Google Scholar 

  173. 173.

    Lim, W. W. et al. Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice. PLoS ONE 15, e0227505 (2020).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  174. 174.

    Zhang, Y. S. et al. STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation. EMBO J. 38, e99595 (2019).

    PubMed Central  PubMed  Google Scholar 

  175. 175.

    Guimbaud, R. et al. Leukemia inhibitory factor involvement in human ulcerative colitis and its potential role in malignant course. Eur. Cytokine Netw. 9, 607–612 (1998).

    CAS  PubMed  Google Scholar 

  176. 176.

    Prieto-Vicente, V. et al. Cardiotrophin-1 attenuates experimental colitis in mice. Clin. Sci. 132, 985–1001 (2018).

    CAS  Article  Google Scholar 

  177. 177.

    Sanchez-Garrido, A. I. et al. Preventive effect of cardiotrophin-1 administration before DSS-induced ulcerative colitis in mice. J. Clin. Med. 8, 2086 (2019).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  178. 178.

    Beigel, F. et al. Oncostatin M mediates STAT3-dependent intestinal epithelial restitution via increased cell proliferation, decreased apoptosis and upregulation of SERPIN family members. PLoS ONE 9, e93498 (2014).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  179. 179.

    Sanchez, A. L. et al. Adenoviral transfer of the murine oncostatin M gene suppresses dextran-sodium sulfate-induced colitis. J. Interferon Cytokine Res. 23, 193–201 (2003).

    CAS  Article  PubMed  Google Scholar 

  180. 180.

    Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  181. 181.

    West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  182. 182.

    Imielinski, M. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41, 1335–1340 (2009).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  183. 183.

    Wang, Z., Wang, L., Fan, R., Zhou, J. & Zhong, J. Association of IL-27 gene three polymorphisms with Crohn’s disease susceptibility in a Chinese Han population. Int. J. Clin. Exp. Pathol. 7, 8952–8957 (2014).

    PubMed Central  PubMed  Google Scholar 

  184. 184.

    Li, C. S. et al. Interleukin-27 polymorphisms are associated with inflammatory bowel diseases in a Korean population. J. Gastroenterol. Hepatol. 24, 1692–1696 (2009).

    CAS  Article  PubMed  Google Scholar 

  185. 185.

    Hanson, M. L. et al. Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology 146, 210–221.e13 (2014).

    CAS  Article  PubMed  Google Scholar 

  186. 186.

    Sasaoka, T. et al. Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G568–G576 (2011).

    CAS  Article  PubMed  Google Scholar 

  187. 187.

    Dambacher, J. et al. Interleukin 31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is upregulated in inflammatory bowel disease. Gut 56, 1257–1265 (2007).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  188. 188.

    Perrigoue, J. G., Zaph, C., Guild, K., Du, Y. & Artis, D. IL-31-IL-31R interactions limit the magnitude of Th2 cytokine-dependent immunity and inflammation following intestinal helminth infection. J. Immunol. 182, 6088–6094 (2009).

    CAS  Article  PubMed  Google Scholar 

  189. 189.

    Nayar, S. et al. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn’s disease. Nature 593, 275–281 (2021).

    CAS  Article  PubMed  Google Scholar 

  190. 190.

    Putoczki, T. L. et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 24, 257–271 (2013).

    CAS  Article  PubMed  Google Scholar 

  191. 191.

    Yoshizaki, A. et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int. J. Oncol. 29, 869–876 (2006).

    CAS  PubMed  Google Scholar 

  192. 192.

    Wei, J. et al. Bazedoxifene as a novel GP130 inhibitor for colon cancer therapy. J. Exp. Clin. Cancer Res. 38, 63 (2019).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  193. 193.

    Thilakasiri, P. et al. Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth. EMBO Mol. Med. 11, e9539 (2019).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  194. 194.

    Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).

    CAS  Article  PubMed  Google Scholar 

  195. 195.

    Corcoran, R. B. et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71, 5020–5029 (2011).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  196. 196.

    Zhang, Y. et al. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res. 73, 6359–6374 (2013).

    CAS  Article  PubMed  Google Scholar 

  197. 197.

    Goumas, F. A. et al. Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. Int. J. Cancer 137, 1035–1046 (2015).

    CAS  Article  PubMed  Google Scholar 

  198. 198.

    Wu, X., Cao, Y., Xiao, H., Li, C. & Lin, J. Bazedoxifene as a novel GP130 inhibitor for pancreatic cancer therapy. Mol. Cancer Ther. 15, 2609–2619 (2016).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  199. 199.

    Judd, L. M. et al. Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Gastroenterology 126, 196–207 (2004).

    CAS  Article  PubMed  Google Scholar 

  200. 200.

    Jenkins, B. J. et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling. Nat. Med. 11, 845–852 (2005).

    CAS  Article  PubMed  Google Scholar 

  201. 201.

    Tebbutt, N. C. et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat. Med. 8, 1089–1097 (2002).

    CAS  Article  PubMed  Google Scholar 

  202. 202.

    Hill, D. G. et al. Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development. Int. J. Cancer 143, 167–178 (2018).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  203. 203.

    Ernst, M. et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J. Clin. Invest. 118, 1727–1738 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  204. 204.

    Jackson, C. B. et al. Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression. J. Pathol. 213, 140–151 (2007).

    CAS  Article  PubMed  Google Scholar 

  205. 205.

    Komoda, H. et al. Interleukin-6 levels in colorectal cancer tissues. World J. Surg. 22, 895–898 (1998).

    CAS  Article  PubMed  Google Scholar 

  206. 206.

    Heikkila, K., Ebrahim, S. & Lawlor, D. A. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur. J. Cancer 44, 937–945 (2008).

    CAS  Article  PubMed  Google Scholar 

  207. 207.

    Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  208. 208.

    Howlett, M. et al. The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development. Gastroenterology 136, 967–977 (2009).

    CAS  Article  PubMed  Google Scholar 

  209. 209.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02641522 (2018).

  210. 210.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02293837 (2021).

  211. 211.

    Wedell-Neergaard, A. S. et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab. 29, 844–855.e3 (2019).

    CAS  Article  PubMed  Google Scholar 

  212. 212.

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/show/NCT01073826 (2016).

  213. 213.

    [No authors listed]. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 46, 1244-1249 (1996).

  214. 214.

    Ettinger, M. P. et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. Jama 289, 1826–1832 (2003).

    CAS  Article  PubMed  Google Scholar 

  215. 215.

    Duff, E. & Baile, C. A. Ciliary neurotrophic factor: a role in obesity? Nutr. Rev. 61, 423–426 (2003).

    Article  PubMed  Google Scholar 

  216. 216.

    Ito, H. et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 126, 989–996; discussion 947 (2004).

    CAS  Article  PubMed  Google Scholar 

  217. 217.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01287897 (2016).

  218. 218.

    Danese, S. et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut 68, 40–48 (2019).

    CAS  Article  Google Scholar 

  219. 219.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01545050 (2020).

  220. 220.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01635621 (2012).

  221. 221.

    Mitsuyama, K. et al. STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Gut 55, 1263–1269 (2006).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  222. 222.

    Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat. Med. 6, 583–588 (2000).

    CAS  Article  Google Scholar 

  223. 223.

    Schreiber, S. et al. Therapeutic interleukin 6 trans-signaling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease. Gastroenterology https://doi.org/10.1053/j.gastro.2021.02.062 (2021).

    Article  PubMed  Google Scholar 

  224. 224.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03235752 (2021).

  225. 225.

    Sands, B. E. et al. Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn’s disease. Gastroenterology 117, 58–64 (1999).

    CAS  Article  PubMed  Google Scholar 

  226. 226.

    Sands, B. E. et al. Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn’s disease. Aliment. Pharmacol. Ther. 16, 399–406 (2002).

    CAS  Article  PubMed  Google Scholar 

  227. 227.

    Herrlinger, K. R. et al. Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn’s disease. Am. J. Gastroenterol. 101, 793–797 (2006).

    CAS  Article  PubMed  Google Scholar 

  228. 228.

    Sandborn, W. J. et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 367, 616–624 (2012).

    CAS  Article  PubMed  Google Scholar 

  229. 229.

    Sandborn, W. J. et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 376, 1723–1736 (2017).

    CAS  Article  PubMed  Google Scholar 

  230. 230.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03281304 (2021).

  231. 231.

    Panes, J. et al. Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut 66, 1049–1059 (2017).

    CAS  Article  PubMed  Google Scholar 

  232. 232.

    Sands, B. E. et al. Peficitinib, an oral janus kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomised, phase 2 study. J. Crohns Colitis 12, 1158–1169 (2018).

    Article  PubMed  Google Scholar 

  233. 233.

    Vermeire, S. et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 389, 266–275 (2017).

    CAS  Article  PubMed  Google Scholar 

  234. 234.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02914600 (2021).

  235. 235.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02914535 (2021).

  236. 236.

    Sandborn, W. J. et al. Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn’s disease. Gastroenterology 158, 2123–2138.e8 (2020).

    CAS  Article  PubMed  Google Scholar 

  237. 237.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03006068 (2021).

  238. 238.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03345836 (2021).

  239. 239.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03675477 (2021).

  240. 240.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03677648 (2020).

  241. 241.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03635112 (2021).

  242. 242.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03920254 (2021).

  243. 243.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03395184 (2021).

  244. 244.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02958865 (2021).

  245. 245.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT04353791 (2021).

  246. 246.

    Wilde, M. I. & Faulds, D. Oprelvekin: a review of its pharmacology and therapeutic potential in chemotherapy-induced thrombocytopenia. BioDrugs 10, 159–171 (1998).

    CAS  Article  PubMed  Google Scholar 

  247. 247.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03490669 (2020).

  248. 248.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT04191421 (2020).

  249. 249.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03382340 (2020).

  250. 250.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02119676 (2018).

  251. 251.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02277093 (2017).

  252. 252.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03522649 (2019).

  253. 253.

    Okusaka, T. et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol. Res. 45, 1283–1291 (2015).

    CAS  Article  PubMed  Google Scholar 

  254. 254.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01839604 (2017).

  255. 255.

    Plimack, E. R. et al. AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors. Oncologist 18, 819–820 (2013).

    PubMed Central  PubMed  Article  Google Scholar 

  256. 256.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01219543 (2013).

  257. 257.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT04358185 (2020).

  258. 258.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT04374877 (2020).

  259. 259.

    Spencer, S. et al. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J. Exp. Med. 216, 1986–1998 (2019).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  260. 260.

    Chen, Y. H. et al. Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome. J. Exp. Med. 217, e20191306 (2020).

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  261. 261.

    Schwerd, T. et al. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J. Exp. Med. 214, 2547–2562 (2017).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  262. 262.

    Shahin, T. et al. Selective loss of function variants in IL6ST cause hyper-IgE syndrome with distinct impairments of T-cell phenotype and function. Haematologica 104, 609–621 (2019).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  263. 263.

    Minegishi, Y. et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25, 745–755 (2006).

    CAS  Article  PubMed  Google Scholar 

  264. 264.

    Boisson-Dupuis, S. et al. Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant. Sci. Immunol. 3, eaau8714 (2018).

    PubMed Central  PubMed  Article  Google Scholar 

  265. 265.

    Minegishi, Y. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007).

    CAS  Article  PubMed  Google Scholar 

  266. 266.

    Fabre, A. et al. Clinical aspects of STAT3 gain-of-function germline mutations: a systematic review. J. Allergy Clin. Immunol. Pract. 7, 1958–1969.e9 (2019).

    Article  PubMed  Google Scholar 

  267. 267.

    Yang, S. et al. Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma. Oncotarget 7, 5461–5469 (2016).

    Article  PubMed  Google Scholar 

  268. 268.

    Ungureanu, D. et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol. 18, 971–976 (2011).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  269. 269.

    Keupp, K. et al. Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis. Mol. Genet. Genomic Med. 1, 223–237 (2013).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  270. 270.

    Brischoux-Boucher, E. et al. IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: resemblances and differences. Clin. Genet. 94, 373–380 (2018).

    CAS  Article  PubMed  Google Scholar 

  271. 271.

    Arita, K. et al. Oncostatin M receptor-β mutations underlie familial primary localized cutaneous amyloidosis. Am. J. Hum. Genet. 82, 73–80 (2008).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  272. 272.

    Dagoneau, N. et al. Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am. J. Hum. Genet. 74, 298–305 (2004).

    CAS  PubMed Central  PubMed  Article  Google Scholar 

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Acknowledgements

D.C. is supported by a predoctoral iPFIS (IFI 19/00048) funded by the Spanish Institute of Health Carlos III (co-funded by the European Social Fund). M.D.G. acknowledges support from a Juan Rodes contract (JR18/00026) funded by the Spanish Institute of Health Carlos III (co-funded by the European Social Fund). This study is supported by MINECO/AEI/FEDER, UE PID2019-110587RB-I00 from the Ministry of Economy and Competitiveness (co-funded by the European Social Fund) and Andalusian Ministry of Economy, Innovation, Science and Employment (P18-RT-4775). S.R.- J. is funded by the German Research Foundation (DFG, project number 80750187 – SFB 841 (project C1). S.R.- J. and C.G. are funded by the German Research Foundation (DFG, project number 125440785 – SFB 877 (projects A1, A10 and A14)).

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Correspondence to Matilde Bustos.

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S.R.-J. has acted as a consultant and speaker for AbbVie, Chugai, Genentech Roche, Pfizer and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein olamkicept together with the company I-Mab. S.R.-J. has stock ownership in CONARIS. C.G. has received a research grant from Corvidia Therapeutics (Waltham, MA, USA) and has acted as a consultant for AbbVie. All other authors declare no competing interests.

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Giraldez, M.D., Carneros, D., Garbers, C. et al. New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nat Rev Gastroenterol Hepatol 18, 787–803 (2021). https://doi.org/10.1038/s41575-021-00473-x

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