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Pro- and anti-inflammatory bioactive lipids imbalance contributes to the pathobiology of autoimmune diseases

Abstract

Autoimmune diseases are driven by TH17 cells that secrete pro-inflammatory cytokines, especially IL-17. Under normal physiological conditions, autoreactive T cells are suppressed by TGF-β and IL-10 secreted by microglia and dendritic cells. When this balance is upset due to injury, infection and other causes, leukocyte recruitment and macrophage activation occurs resulting in secretion of pro-inflammatory IL-6, TNF-α, IL-17 and PGE2, LTs (leukotrienes) accompanied by a deficiency of anti-inflammatory LXA4, resolvins, protecting, and maresins. PGE2 facilitates TH1 cell differentiation and promotes immune-mediated inflammation through TH17 expansion. There is evidence to suggest that autoimmune diseases can be suppressed by anti-inflammatory bioactive lipids LXA4, resolvins, protecting, and maresins. These results imply that systemic and/or local application of LXA4, resolvins, protecting, and maresins and administration of their precursors AA/EPA/DHA could form a potential therapeutic approach in the prevention and treatment of autoimmune diseases.

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Fig. 1: A peripheral lymphocyte showing the presence of micronucleus (MN) (arrow) in its cytoplasm.
Fig. 2: cGAS-STING pathway in autoimmune process.
Fig. 3: Scheme showing EFA metabolism, interaction, and feedback regulation among immunocytes, cytokines, various bioactive lipids (BALs), and inflammation.
Fig. 4: Factors that have a regulatory role in the formation of different subsets of T helper cells.
Fig. 5: Scheme showing polarization of Naive CD+ T cells to Treg and TH17 cells and factors influencing this process.
Fig. 6: Lipoxin biosynthesis and structures.
Fig. 7: Effect of PGE1 and PGE2 on the generation of LXA4.
Fig. 8: Effect of various unsaturated fatty acids on the generation of LXA4 inhibited by streptozotocin (STZ)-treated RIN (rat inulinoma) cells in vitro.

References

  1. Mackenzie K, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548:461–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. Das UN. Molecular pathobiology of scleritis and its therapeutic implications. Int J Ophthalmol. 2020;13:163–75. https://doi.org/10.18240/ijo.2020.01.23.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498:380–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. Civril F, Deimling T, de Oliveira Mann C, Ablasser A, Moldt M, Witte G, et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature. 2013;498:332–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. Ablasser A, Schmid-Burgk J, Hemmerling I, Horvath GL, Schmidt T, Latz E, et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature. 2013;503:530–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. Schoggins J, MacDuff D, Imanaka N, Gainey MD, Shrestha B, Eitson JL, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature. 2014;505:691–5.

    CAS  PubMed  Article  Google Scholar 

  7. Harding S, Benci J, Irianto J, Discher DE, Minn AJ, Greenberg RA. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548:466–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. Karaman A, Kadi M, Kara F. Sister chromatid exchange and micronucleus studies in patients with Behçet’s disease. J Cutan Pathol. 2009;36:831–7.

    PubMed  Article  Google Scholar 

  9. Hamurcu Z, Dönmez-Altuntas H, Borlu M, Demirtas H, Asçioslu O. Micronucleus frequency in the oral mucosa and lymphocytes of patients with Behçet’s disease. Clin Exp Dermatol. 2005;30:565–9.

    CAS  PubMed  Article  Google Scholar 

  10. Sommer S, Buraczewska I, Kruszewski M. Micronucleus assay: the state of art, and future directions. Int J Mol Sci. 2020;21:1534.

    CAS  Article  PubMed Central  Google Scholar 

  11. Franzke B, Schwingshackl L, Wagner KH. Chromosomal damage measured by the cytokinesis block micronucleus cytome assay in diabetes and obesity - a systematic review and meta-analysis. Mutat Res Rev Mutat Res. 2020;786:108343.

    CAS  PubMed  Article  Google Scholar 

  12. Toljic M, Egic A, Munjas J, Karadzov Orlic N, Milovanovic Z, Radenkovic A, et al. Increased oxidative stress and cytokinesis-block micronucleus cytome assay parameters in pregnant women with gestational diabetes mellitus and gestational arterial hypertension. Reprod Toxicol. 2017;71:55–62.

    CAS  PubMed  Article  Google Scholar 

  13. Vu BG, Stach CS, Kulhankova K, Salgado-Pabón W, Klingelhutz AJ, Schlievert PM. Chronic superantigen exposure induces systemic inflammation, elevated bloodstream endotoxin, and abnormal glucose tolerance in rabbits: possible role in diabetes. mBio 2015;6:e02554.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  14. Hui J, Qu YY, Tang N, Liu YM, Zhong H, Wang LM, et al. Association of cytomegalovirus infection with hypertension risk: a meta-analysis. Wien Klin Wochenschr. 2016;128:586–91.

    PubMed  Article  PubMed Central  Google Scholar 

  15. Torres-Bugarín O, Macriz Romero N, Ramos Ibarra ML, Flores-García A, Valdez Aburto P, Zavala-Cerna MG. Genotoxic effect in autoimmune diseases evaluated by the micronucleus test assay: our experience and literature review. Biomed Res Int. 2015;2015:194031.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  16. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.

    CAS  PubMed  Article  Google Scholar 

  17. Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol. 2003;73:213–24.

    CAS  PubMed  Article  Google Scholar 

  18. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992;356:768–74.

    CAS  PubMed  Article  Google Scholar 

  19. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro IL-beta. Mol Cell. 2002;10:417–26.

    CAS  PubMed  Article  Google Scholar 

  20. Liu ZF, Zhang F, Guo DD, Pan XM, Bi HS. Cytotoxic effect of specific T cells from mice with experimental autoimmune uveitis on murine photoreceptor cells. Int J Ophthalmol. 2020;13:1180–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. Dou Z, Ghosh K, Vizioli M, Zhu J, Sen P, Wangensteen KJ, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017;550:402–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Tigano M, Vargas DC, Tremblay-Belzile S, Fu Y, Sfeir A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature. 2021;591:477–81.

    CAS  PubMed  Article  Google Scholar 

  23. Das UN, Devi GR, Rao KP, Rao MS. Prostaglandins and their precursors can modify genetic damage induced by gamma-radiation and benzo(a)pyrene. Prostaglandins. 1985;29:911–20.

    CAS  PubMed  Article  Google Scholar 

  24. Koratkar R, Das UN, Sagar PS, Ramesh G, Padma M, Kumar GS, et al. Prostacyclin is a potent anti-mutagen. Prostaglandins Leukot Ess Fat Acids. 1993;48:175–84.

    CAS  Article  Google Scholar 

  25. Devi GR, Das UN, Rao KP, Rao MS. Prostaglandins and mutagenesis: prevention and/or reversibility of genetic damage induced by benzo (a) pyrene in the bone marrow cells of mice by prostaglandins El. Prostaglandins Leukotrienes Med. 1984;15:287–92.

    Article  Google Scholar 

  26. Devi GR, Das UN, Rao KP, Rao MS. Prostaglandins and mutagenesis: modification of phenytoin-induced genetic damage by Prostaglandins in lymphocyte cultures. Prostaglandins Leukotrienes Med. 1984;15:109–13.

    Article  Google Scholar 

  27. Das UN, Rao KP. Effect of γ-linolenic acid and prostaglandins E1 on gamma-radiation and chemical-induced genetic damage to the bone marrow cells of mice. Prostaglandins Leukot Ess Fat Acids. 2006;74:165–73.

    CAS  Article  Google Scholar 

  28. Shivani P, Rao KP, Chaudhury JR, Ahmed J, Rao BR, Kanjilal S, et al. Effect of polyunsaturated fatty acids on diphenyl hydantoin-induced genetic damage in-vitro and in vivo. Prostaglandins Leukot Ess Fat Acids. 2009;80:43–50.

    Article  CAS  Google Scholar 

  29. Das UN. Tumoricidal action of cis-unsaturated fatty acids and their relationship to free radicals and lipid peroxidation. Cancer Lett. 1991;56:235–43.

    CAS  PubMed  Article  Google Scholar 

  30. Das UN, Huang Y-S, Bēgin ME, Ells G, Horrobin DF. Uptake and distribution of cis-unsaturated fatty acids and their effect on free radical generation in normal and tumor cells in vitro. Free Radic Biol Med. 1987;3:9–14.

    CAS  PubMed  Article  Google Scholar 

  31. Das UN. Molecular biochemical aspects of cancer. New York: Humana Press; 2020.

  32. Das UN. Essential fatty acids enhance free radical generation and lipid peroxidation to induce apoptosis of tumor cells. Clin Lipidol. 2011;6:463–89.

    CAS  Article  Google Scholar 

  33. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nat Cell Biol. 2017;547:453–7.

    CAS  Google Scholar 

  34. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nat Cell Biol. 2017;551:247–50.

    CAS  Google Scholar 

  35. Ramos-Remus C, Dorazco-Barragan G, Aceves-Avila FJ, Alcaraz-Lopez F, Fuentes-Ramirez F, Michel-Diaz J, et al. Genotoxicity assessment using micronuclei assay in rheumatoid arthritis patients. Clin Exp Rheumatol. 2002;20:208–12.

    CAS  PubMed  Google Scholar 

  36. Al-Rawi ZS, Gorial FI, Tawfiq RF, Mohammed AK, Al-Naaimi AS, Al’aadhmi MA, et al. Brief report: a novel application of buccal micronucleus cytome assay in systemic lupus erythematosus: a case-control study. Arthritis Rheumatol. 2014;66:2837–41.

    PubMed  Article  Google Scholar 

  37. Baig A, Avlasevich SL, Torous DK, Bemis JC, Saubermann LJ, Lovell DP, et al. Assessment of systemic genetic damage in pediatric inflammatory bowel disease. Environ Mol Mutagen. 2020;61:901–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. Chmurzyńska A. The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. J Appl Genet. 2006;47:39–48.

    PubMed  Article  Google Scholar 

  39. Smathers RL, Petersen DR. The human fatty acid-binding protein family: evolutionary divergences and functions. Hum Genomics. 2011;5:170–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. Stolp B, Thelen F, Ficht X, Altenburger LM, Ruef N, Inavalli VVGK, et al. Salivary gland macrophages and tissue-resident CD8+ T cells cooperate for homeostatic organ surveillance. Sci Immunol. 2020;5:eaaz4371.

    CAS  PubMed  Article  Google Scholar 

  41. Coonrod JD. Rôle of surfactant free fatty acids in antimicrobial defenses. Eur J Respir Dis Suppl. 1987;153:209–14.

    CAS  PubMed  Google Scholar 

  42. Frizzell H, Fonseca R, Christo SN, Evrard M, Cruz-Gomez S, Zanluqui NG, et al. Organ-specific isoform selection of fatty acid–binding proteins in tissue-resident lymphocytes. Sci Immunol. 2020;5:eaay9283.

    CAS  PubMed  Article  Google Scholar 

  43. Furuhashi M, Hotamisligil G. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008;7:489–503.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. Lee GS, Pan Y, Scanlon MJ, Porter CJH, Nicolazzo JA. Fatty acid-binding protein 5 mediates the uptake of fatty acids, but not drugs, into human brain endothelial cells. J Pharm Sci. 2018;107:1185–93.

    CAS  PubMed  Article  Google Scholar 

  45. Storch J, Corsico B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr. 2008;28:73–95.

    CAS  PubMed  Article  Google Scholar 

  46. Rolph MS, Young TR, Shum BO, Gorgun CZ, Schmitz-Peiffer C, Ramshaw IA, et al. Regulation of dendritic cell function and T cell priming by the fatty acid-binding protein AP2. J Immunol. 2006;177:7794–801.

    CAS  PubMed  Article  Google Scholar 

  47. Rao E, Singh P, Li Y, Zhang Y, Chi YI, Suttles J, et al. Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis. BMC Immunol. 2015;16:28.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  48. Pan Y, Tian T, Park C, Lofftus SY, Mei S, Liu X, et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature. 2017;543:252–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. Moore SM, Holt VV, Malpass LR, Hines IN, Wheeler MD. Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages. Mol Immunol. 2015;67:265–75.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. Zhang Y, Sun Y, Rao E, Yan F, Li Q, Zhang Y, et al. Fatty acid-binding protein E-FABP restricts tumor growth by promoting IFN-β responses in tumor-associated macrophages. Cancer Res. 2014;74:2986–98.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. Gerriets V, Kishton R, Johnson M, Cohen S, Siska PJ, Nichols AG, et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol. 2016;17:1459–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186:3299–303.

    CAS  PubMed  Article  Google Scholar 

  53. Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab. 2020;31:422–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.

    CAS  PubMed  Article  Google Scholar 

  55. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.

    CAS  PubMed  Article  Google Scholar 

  56. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity. 2011;34:566–78.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. Li MO, Wan YY, Flavell RA. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity. 2007;26:579–91.

    CAS  PubMed  Article  Google Scholar 

  58. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008;28:546–58.

    CAS  PubMed  Article  Google Scholar 

  59. Das UN. Molecular biochemical aspects of cancer. NY: Humana Press; 2020.

  60. Bettelli E, Kom T, Oukka M, Kuchroo VK. Induction and effector functions of TH17 cells. Nature. 2008;453:1051–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. Margarita Dominguez-Villar M, Hafler DA. An innate role for IL-17. Science. 2011;332:47–48.

    PubMed  Article  Google Scholar 

  62. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673–82.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 2003;171:6173–7.

    CAS  PubMed  Article  Google Scholar 

  64. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177:566–73.

    CAS  PubMed  Article  Google Scholar 

  65. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, et al. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999;42:963–70.

    CAS  PubMed  Article  Google Scholar 

  66. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8:500–8.

    CAS  PubMed  Article  Google Scholar 

  67. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8:950–7.

    CAS  PubMed  Article  Google Scholar 

  69. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13:1173–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–89.

    CAS  PubMed  Article  Google Scholar 

  71. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.

    CAS  PubMed  Article  Google Scholar 

  72. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007;26:371–81.

    CAS  PubMed  Article  Google Scholar 

  73. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–60.

    CAS  PubMed  Article  Google Scholar 

  74. Kleinschek MA, Owyang AM, Joyce-Shaikh B, Langrish CL, Chen Y, Gorman DM, et al. IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med. 2007;204:161–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol. 2006;7:929–36.

    CAS  PubMed  Article  Google Scholar 

  76. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol. 2006;7:937–45.

    CAS  PubMed  Article  Google Scholar 

  77. Wang R, Hasnain SZ, Tong H, Das I, Che-Hao Chen A, Oancea I, et al. Neutralizing IL-23 Is Superior to Blocking IL-17 in Suppressing Intestinal Inflammation in a Spontaneous Murine Colitis Model. Inflamm Bowel Dis. 2015;21:973–84.

    PubMed  Article  Google Scholar 

  78. Das UN. Molecular basis of health and disease. New York: Springer; 2011.

  79. Das UN. Inhibition of sensitized lymphocyte response to sperm antigen(s) by prostaglandins. IRCS Med Sci. 1981;9:1087.

    CAS  Google Scholar 

  80. Kumar SG, Das UN. Effect of prostaglandins and their precursors on the proliferation of human lymphocytes and their secretion of tumor necrosis factor and various interleukins. Prostaglandins Leukot Ess Fat Acids. 1994;50:331–4.

    CAS  Article  Google Scholar 

  81. Das UN. HLA-DR expression, cytokines and bioactive lipids in sepsis. Arch Med Sci. 2014;10:325–35. 2

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. Narumiya S. Physiology and pathophysiology of prostanoid receptors. Proc Jpn Acad Ser B. 2007;83:296–319.

    CAS  Article  Google Scholar 

  83. Goodwin JS, Ceuppens J. Regulation of the immune response by prostaglandins. J Clin Immunol. 1983;3:295–315.

    CAS  PubMed  Article  Google Scholar 

  84. Betz M, Fox BS. Prostaglandin E2 inhibits production of TH1 lymphokines but not of Th2 lymphokines. J Immunol. 1991;146:108–13.

    CAS  PubMed  Google Scholar 

  85. Gold KN, Weyand CM, Goronzy JJ. Modulation of helper T cell function by prostaglandins. Arthritis Rheum. 1994;37:925–33.

    CAS  PubMed  Article  Google Scholar 

  86. Hilkens CM, Vermeulen H, van Neerven RJ, Snijdewint FG, Wierenga EA, Kapsenberg ML. Differential modulation of T helper type 1 (TH1) and T helper type 2 (TH2) cytokine secretion by prostaglandin E2 critically depends on interleukin-2. Eur J Immunol. 1995;25:59–63.

    CAS  PubMed  Article  Google Scholar 

  87. Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, et al. Prostaglandin E2–EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion. Nat Med. 2009;15:633–40.

    CAS  PubMed  Article  Google Scholar 

  88. Kabashima K, Sakata D, Nagamachi M, Miyachi Y, Inaba K, Narumiya S. Prostaglandin E2–EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Nat Med. 2003;9:744–9.

    CAS  PubMed  Article  Google Scholar 

  89. Herve´ M, Angeli V, Pinzar E, Wintjens R, Faveeuw C, Narumiya S, et al. Pivotal roles of the parasite PGD2 synthase and of the host D prostanoid receptor 1 in schistosome immune evasion. Eur J Immunol. 2003;33:2764–72.

    PubMed  Article  CAS  Google Scholar 

  90. Kabashima K, Murata T, Tanaka H, Matsuoka T, Sakata D, Yoshida N, et al. Thromboxane A2 modulates interaction of dendritic cells and T cells and regulates acquired immunity. Nat Immunol. 2003;4:694–701.

    CAS  PubMed  Article  Google Scholar 

  91. Moalli F, Cupovic J, Thelen F, Halbherr P, Fukui Y, Narumiya S, et al. Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell-dendritic cell interactions. J Exp Med. 2014;211:2507–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. Chizzolini C, Chicheportiche R, Alvarez M, de Rham C, Roux-Lombard P, Ferrari-Lacraz S, et al. Prostaglandin E2 synergistically with interleukin-23 favors human TH17 expansion. Blood. 2008;112:3696–703.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, et al. Prostaglandin E2 regulates TH17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med. 2009;206:535–48.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of immunity. Trends Immunol. 2002;23:144–50.

    CAS  PubMed  Article  Google Scholar 

  95. Kalinski P. Regulation of immune responses by prostaglandin e2. J Immunol. 2012;188:21–28.

    CAS  PubMed  Article  Google Scholar 

  96. Linnemeyer PA, Pollack SB. Prostaglandin E2-induced changes in the phenotype, morphology, and lytic activity of IL-2-activated natural killer cells. J Immunol. 1993;150:3747–54.

    CAS  PubMed  Google Scholar 

  97. Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E2 and T cells: friends or foes? Immunol Cell Biol. 2012;90:579–86.

    CAS  PubMed  Article  Google Scholar 

  98. Strassmann G, Patil-Koota V, Finkelman F, Fong M, Kambayashi T. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J Exp Med. 1994;180:2365–70.

    CAS  PubMed  Article  Google Scholar 

  99. Demeure CE, Yang LP, Desjardins C, Raynauld P, Delespesse G. Prostaglandin E2 primes naive T cells for the production of anti-inflammatory cytokines. Eur J Immunol. 1997;27:3526–31.

    CAS  PubMed  Article  Google Scholar 

  100. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. Rahmouni S, Aandahl EM, Nayjib B, Zeddou M, Giannini S, Verlaet M, et al. Cyclo-oxygenase type 2-dependent prostaglandin E2 secretion is involved in retrovirus-induced T-cell dysfunction in mice. Biochem J. 2004;384:469–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. Tuo J, Tuaillon N, Shen D, Chan CC. Endotoxin-induced uveitis in cyclooxygenase-2-deficient mice. Investig Ophthalmol Vis Sci. 2004;45:2306–13.

    Article  Google Scholar 

  103. Eom Y, Lee DY, Kang BR, Heo JH, Shin KH, Kim HM, et al. Comparison of aqueous levels of inflammatory mediators between toxic anterior segment syndrome and endotoxin-induced uveitis animal models. Investig Ophthalmol Vis Sci. 2014;55:6704–10.

    Article  Google Scholar 

  104. Gaillard T, Mülsch A, Klein H, Decker K. Regulation by prostaglandin E2 of cytokine-elicited nitric oxide synthesis in rat liver macrophages. Biol Chem Hoppe Seyler. 1992;373:897–902.

    CAS  PubMed  Article  Google Scholar 

  105. Stadler J, Harbrecht BG, Di Silvio M, Curran RD, Jordan ML, Simmons RL, et al. Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells. J Leukoc Biol. 1993;53:165–72.

    CAS  PubMed  Article  Google Scholar 

  106. Tetsuka T, Daphna-Iken D, Miller BW, Guan Z, Baier LD, Morrison AR. Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. J Clin Investig. 1996;97:2051–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. Wilson KT, Vaandrager AB, De Vente J, Musch MW, De Jonge HR, Chang EB. Production and localization of cGMP and PGE2 in nitroprusside-stimulated rat colonic ion transport. Am J Physiol. 1996;270:C832–C840. 3

    CAS  PubMed  Article  Google Scholar 

  108. Sautebin L, Ialenti A, Ianaro A, Di Rosa M. Endogenous nitric oxide increases prostaglandin biosynthesis in carrageenin rat paw oedema. Eur J Pharmacol. 1995;286:219–22.

    CAS  PubMed  Article  Google Scholar 

  109. Biondi C, Fiorini S, Pavan B, Ferretti ME, Barion P, Vesce F. Interactions between the nitric oxide and prostaglandin E2 biosynthetic pathways in human amnion-like WISH cells. J Reprod Immunol. 2003;60:35–52.

    CAS  PubMed  Article  Google Scholar 

  110. Du Y, Sarthy VP, Kern TS. Interaction between NO and COX pathways in retinal cells exposed to elevated glucose and retina of diabetic rats. Am J Physiol Regul Integr Comp Physiol. 2004;287:R735–R741.

    CAS  PubMed  Article  Google Scholar 

  111. Chien CC, Shen SC, Yang LY, Chen YC. Prostaglandins as negative regulators against lipopolysaccharide, lipoteichoic acid, and peptidoglycan-induced inducible nitric oxide synthase/nitric oxide production through reactive oxygen species-dependent heme oxygenase 1 expression in macrophages. Shock. 2012;38:549–58.

    CAS  PubMed  Article  Google Scholar 

  112. Stæhr M, Hansen PB, Madsen K, Vanhoutte PM, Nüsing RM, Jensen BL. Deletion of cyclooxygenase-2 in the mouse increases arterial blood pressure with no impairment in renal NO production in response to chronic high salt intake. Am J Physiol Regul Integr Comp Physiol. 2013;304:R899–R907.

    PubMed  Article  CAS  Google Scholar 

  113. Harizi H, Norbert G. Inhibition of IL-6, TNF-alpha, and cyclooxygenase-2 protein expression by prostaglandin E2-induced IL-10 in bone marrow-derived dendritic cells. Cell Immunol. 2004;228:99–109.

    PubMed  Article  CAS  Google Scholar 

  114. Harizi H, Juzan M, Pitard V, Moreau JF, Gualde N. Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. J Immunol. 2002;168:2255–63.

    CAS  PubMed  Article  Google Scholar 

  115. Kanda N, Koike S, Watanabe S. IL-17 suppresses TNF-alpha-induced CCL27 production through induction of COX-2 in human keratinocytes. J Allergy Clin Immunol. 2005;116:1144–50.

    CAS  PubMed  Article  Google Scholar 

  116. Khayrullina T, Yen JH, Jing H, Ganea D. In vitro differentiation of dendritic cells in the presence of prostaglandin E2 alters the IL-12/IL-23 balance and promotes differentiation of Th17 cells. J Immunol. 2008;181:721–35.

    CAS  PubMed  Article  Google Scholar 

  117. Chen H, Qin J, Wei P, Zhang J, Li Q, Fu L, et al. Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells. Prostaglandins Leukot Ess Fat Acids. 2009;80:195–200.

    CAS  Article  Google Scholar 

  118. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 1993;90:7240–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. Swierkosz TA, Mitchell JA, Warner TD, Botting RM, Vane JR. Co-induction of nitric oxide synthase and cyclo-oxygenase: interactions between nitric oxide and prostanoids. Br J Pharmacol. 1995;114:1335–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. Mollace V, Colasanti M, Muscoli C, Lauro GM, Iannone M, Rotiroti D, et al. The effect of nitric oxide on cytokine-induced release of PGE2 by human cultured astroglial cells. Br J Pharmacol. 1998;124:742–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. Marcinkiewicz J. Regulation of cytokine production by eicosanoids and nitric oxide. Arch Immunol Ther Exp (Warsz). 1997;45:163–7.

    CAS  Google Scholar 

  122. Tanaka M, Ishibashi H, Hirata Y, Miki K, Kudo J, Niho Y. Tumor necrosis factor production by rat Kupffer cells-regulation by lipopolysaccharide, macrophage activating factor and prostaglandin E2. J Clin Lab Immunol. 1996;48:17–31.

    CAS  PubMed  Google Scholar 

  123. Liu XH, Kirschenbaum A, Lu M, Yao S, Klausner A, Preston C, et al. Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway. Biochem Biophys Res Commun. 2002;290:249–55.

    CAS  PubMed  Article  Google Scholar 

  124. Reznikov LL, Kim SH, Westcott JY, Frishman J, Fantuzzi G, Novick D, et al. IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma. Proc Natl Acad Sci USA 2000;97:2174–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. Perkins DJ, Kniss DA. Blockade of nitric oxide formation down-regulates cyclooxygenase-2 and decreases PGE2 biosynthesis in macrophages. J Leukoc Biol. 1999;65:792–9.

    CAS  PubMed  Article  Google Scholar 

  126. Sakurai T, Tamura K, Kogo H. Vascular endothelial growth factor increases messenger RNAs encoding cyclooxygenase-II and membrane-associated prostaglandin E synthase in rat luteal cells. J Endocrinol. 2004;183:527–33.

    CAS  PubMed  Article  Google Scholar 

  127. Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A, Prasanna SJ. Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism. Sci Rep. 2016;6:38308 https://doi.org/10.1038/srep38308.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. Park HJ, Kim J, Saima FT, Rhee KJ, Hwang S, Kim MY, et al. Adipose-derived stem cells ameliorate colitis by suppression of inflammasome formation and regulation of M1-macrophage population through prostaglandin E2. Biochem Biophys Res Commun. 2018;498:988–95.

    CAS  PubMed  Article  Google Scholar 

  129. An JH, Song WJ, Li Q, Kim SM, Yang JI, Ryu MO, et al. Prostaglandin E2 secreted from feline adipose tissue-derived mesenchymal stem cells alleviate DSS-induced colitis by increasing regulatory T cells in mice. BMC Vet Res. 2018;14:354.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. Rozenberg A, Rezk A, Boivin MN, Darlington PJ, Nyirenda M, Li R, et al. Human mesenchymal stem cells impact Th17 and Th1 responses through a prostaglandin E2 and myeloid-dependent mechanism. Stem Cells Transl Med. 2016;5:1506–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. Phipps RP, Stein SH, Roper RL. A new view of prostaglandin E regulation of the immune response. Immunol Today. 1991;12:349–52.

    CAS  PubMed  Article  Google Scholar 

  132. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–49.

    PubMed  Article  CAS  Google Scholar 

  133. Ylöstalo JH, Bartosh TJ, Coble K, Prockop DJ. Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an antiinflammatory phenotype. Stem Cells. 2012;30:2283–96.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  134. Poloso NJ, Urquhart P, Nicolaou A, Wang J, Woodward DF. PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4). Mol Immunol. 2013;54:284–95.

    CAS  PubMed  Article  Google Scholar 

  135. Kalim KW, Groettrup M. Prostaglandin E2 inhibits IL-23 and IL-12 production by human monocytes through down-regulation of their common p40 subunit. Mol Immunol. 2013;53:274–82.

    CAS  PubMed  Article  Google Scholar 

  136. Loynes CA, Lee JA, Robertson AL, Steel MJ, Ellett F, Feng Y, et al. PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo. Sci Adv. 2018;4:eaar8320. https://doi.org/10.1126/sciadv.aar8320.

  137. Chan MM-Y, Moore AR. Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production. J Immunol. 2010;184:6418–26.

    CAS  PubMed  Article  Google Scholar 

  138. Das UN. Current and emerging strategies for the treatment and management of systemic lupus erythematosus based on molecular signatures of acute and chronic inflammation. J Inflamm Res. 2010;3:143–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. Lefkowitz DL, Lefkowitz SS. Macrophage-neutrophil interaction: a paradigm for chronic inflammation revisited. Immunol Cell Biol. 2001;79:502–6.

    CAS  PubMed  Article  Google Scholar 

  140. Romano M, Serhan CN. Lipoxin generation by permeabilized human platelets. Biochemistry. 1992;31:8269–77.

    CAS  PubMed  Article  Google Scholar 

  141. Stables MJ, Gilroy DW. Old and new generation lipid mediators in acute inflammation and resolution. Prog Lipid Res. 2011;50:35–51.

    CAS  PubMed  Article  Google Scholar 

  142. Serhan CN, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci USA 1984;81:5335–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. Levy BD, Romano M, Chapman HA, Reilly JJ, Drazen J, Serhan CN. Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins. J Clin Investig. 1993;92:1572–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. Loynes CA, Lee JA, Robertson AL, Steel MJ, Ellett F, Feng Y, et al. PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo. Sci Adv. 2018;4:eaar8320.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999;5:698–701.

    CAS  PubMed  Article  Google Scholar 

  146. Dai S, Zhu M, Wu R, Lin D, Huang Z, Ren L, et al. Lipoxin A4 suppresses IL-1β-induced cyclooxygenase-2 expression through inhibition of p38 MAPK activation in endometriosis. Reprod Sci. 2019;26:1640–9.

    CAS  PubMed  Article  Google Scholar 

  147. Polese B, Thurairajah B, Zhang H, Soo CL, McMahon CA, Fontes G, et al. Prostaglandin E2 amplifies IL-17 production by γδ T cells during barrier inflammation. Cell Rep. 2021;36:109456.

    CAS  PubMed  Article  Google Scholar 

  148. Du B, Zhu M, Li Y, Li G, Xi X. The prostaglandin E2 increases the production of IL-17 and the expression of costimulatory molecules on γδ T cells in rheumatoid arthritis. Scand J Immunol. 2020;91:e12872.

    PubMed  Google Scholar 

  149. Maseda D, Johnson EM, Nyhoff LE, Baron B, Kojima F, Wilhelm AJ, et al. mPGES1-dependent prostaglandin E2 (PGE2) controls antigen-specific Th17 and Th1 responses by regulating T autocrine and paracrine PGE2 production. J Immunol. 2018;200:725–36.

    CAS  PubMed  Article  Google Scholar 

  150. Shi Y, Pan H, Zhang HZ, Zhao XY, Jin J, Wang HY. Lipoxin A4 mitigates experimental autoimmune myocarditis by regulating inflammatory response, NF-κB and PI3K/Akt signaling pathway in mice. Eur Rev Med Pharmacol Sci. 2017;21:1850–9.

    CAS  PubMed  Google Scholar 

  151. Gao Y, Min K, Zhang Y, Su J, Greenwood M, Gronert K. Female-specific downregulation of tissue polymorphonuclear neutrophils drives impaired regulatory T cell and amplified effector T cell responses in autoimmune dry eye disease. J Immunol. 2015;195:3086–99.

    CAS  PubMed  Article  Google Scholar 

  152. Gao Y, Su J, Zhang Y, Chan A, Sin JH, Wu D, et al. Dietary DHA amplifies LXA4 circuits in tissues and lymph node PMN and is protective in immune-driven dry eye disease. Mucosal Immunol. 2018;11:1674–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. Lee JY, Jung YW, Jeong I, Joh JS, Sim SY, Choi B, et al. Immune parameters differentiating active from latent tuberculosis infection in humans. Tuberculosis. 2015;95:758–63.

    CAS  PubMed  Article  Google Scholar 

  154. Kim K, Perera R, Tan DB, Fernandez S, Seddiki N, Waring J, et al. Circulating mycobacterial-reactive CD4+ T cells with an immunosuppressive phenotype are higher in active tuberculosis than latent tuberculosis infection. Tuberculosis. 2014;94:494–501.

    CAS  PubMed  Article  Google Scholar 

  155. Marin ND, París SC, Vélez VM, Rojas CA, Rojas M, García LF. Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. Tuberculosis. 2010;90:252–61.

    CAS  PubMed  Article  Google Scholar 

  156. Gerosa F, Nisii C, Righetti S, Micciolo R, Marchesini M, Cazzadori A, et al. CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol. 1999;92:224–34.

    CAS  PubMed  Article  Google Scholar 

  157. Berner B, Akça D, Jung T, Muller GA, Reuss-Borst MA. Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry. J Rheumatol. 2000;27:1128–35.

    CAS  PubMed  Google Scholar 

  158. Khader SA, Cooper AM. IL-23 and IL-17 in tuberculosis. Cytokine. 2008;41:79–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. Wei L, Liu M, Xiong H, Peng B. Up-regulation of IL-23 expression in human dental pulp fibroblasts by IL-17 via activation of the NF-κB and MAPK pathways. Int Endod J. 2018;51:622–31.

    CAS  PubMed  Article  Google Scholar 

  160. Zhu L, Wu Y, Wei H, Xing X, Zhan N, Xiong H, et al. IL-17R activation of human periodontal ligament fibroblasts induces IL-23 p19 production: differential involvement of NF-κB versus JNK/AP-1 pathways. Mol Immunol. 2011;48:647–56.

    CAS  PubMed  Article  Google Scholar 

  161. Liu FL, Chen CH, Chu SJ, Chen JH, Lai JH, Sytwu HK, et al. Interleukin (IL)-23 p19 expression induced by IL-1beta in human fibroblast-like synoviocytes with rheumatoid arthritis via active nuclear factor-kappaB and AP-1 dependent pathway. Rheumatology. 2007;46:1266–73.

    CAS  PubMed  Article  Google Scholar 

  162. Kim HR, Cho ML, Kim KW, Juhn JY, Hwang SY, Yoon CH, et al. IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase-, NF-kappaB- and p38 MAPK-dependent signalling pathways. Rheumatology. 2007;46:57–64.

    CAS  PubMed  Article  Google Scholar 

  163. Xu J, Duan X, Hu F, Poorun D, Liu X, Wang X, et al. Resolvin D1 attenuates imiquimod-induced mice psoriasiform dermatitis through MAPKs and NF-κB pathways. J Dermatol Sci. 2018;89:127–35.

    CAS  PubMed  Article  Google Scholar 

  164. Naveen KVG, Naidu VGM, Das UN. Arachidonic acid and lipoxin A4 attenuate streptozotocin-induced cytotoxicity to RIN5F cells in vitro and type 1 and type 2 diabetes mellitus in vivo. Nutrition. 2017;35:61–80.

    Article  CAS  Google Scholar 

  165. Ali M, Yang F, Jansen JA, Walboomers XF. Lipoxin suppresses inflammation via the TLR4/MyD88/NF-κB pathway in periodontal ligament cells. Oral Dis. 2020;26:429–38.

    PubMed  Article  Google Scholar 

  166. Chen Y, Zheng Y, Xin L, Zhong S, Liu A, Lai W, et al. 15-epi-lipoxin A4 inhibits TNF-α-induced tissue factor expression via the PI3K/AKT/ NF-κB axis in human umbilical vein endothelial cells. Biomed Pharmacother. 2019;117:109099.

    CAS  PubMed  Article  Google Scholar 

  167. Hu F, Liu XX, Wang X, Alashkar M, Zhang S, Xu JT, et al. Lipoxin A4 inhibits proliferation and inflammatory cytokine/chemokine production of human epidermal keratinocytes associated with the ERK1/2 and NF-κB pathways. J Dermatol Sci. 2015;78:181–8.

    CAS  PubMed  Article  Google Scholar 

  168. Hao H, Xu F, Hao J, He YQ, Zhou XY, Dai H, et al. Lipoxin A4 suppresses lipopolysaccharide-induced hela cell proliferation and migration via NF-κB pathway. Inflammation. 2015;38:400–8.

    CAS  PubMed  Article  Google Scholar 

  169. Naveen KVG, Naidu VGM, Das UN. Amelioration of streptozotocin-induced type 2 diabetes mellitus in Wistar rats by arachidonic acid. Biochem Biophys Res Commun. 2018;496:105–13.

    Article  CAS  Google Scholar 

  170. Naveen GV, Das UN. Arachidonic acid rich ARASCO oil has anti-inflammatory and anti-diabetic actions against high fat diet-induced type 2 diabetes mellitus in Wistar rats. Nutrition. 2019;66:203–18.

    Article  CAS  Google Scholar 

  171. Das UN. Arachidonic acid and lipoxin A4 as possible endogenous anti-diabetic molecules. Prostaglandins Leukot Essent Fat Acids 2013;88:201–10.

    CAS  Article  Google Scholar 

  172. Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation. Nat Immunol. 2008;9:873–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  173. Flesher RP, Herbert C, Kumar RK. Resolvin E1 promotes resolution of inflammation in a mouse model of an acute exacerbation of allergic asthma. Clin Sci. 2014;126:805–14.

    CAS  Article  Google Scholar 

  174. Das UN. Bioactive lipids in intervertebral disc degeneration and its therapeutic implications. Biosci Rep. 2019;39:BSR20192117.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  175. Kurtoğlu EL, Kayhan B, Gül M, Kayhan B, Akdoğan Kayhan M, Karaca ZM. et al. A bioactive product lipoxin A4 attenuates liver fibrosis in an experimental model by regulating immune response and modulating the expression of regeneration genes. Turk J Gastroenterol. 2019;30:745–57.

    PubMed  Article  Google Scholar 

  176. Ishizuka T, Hisada T, Aoki H, Mori M. Resolvin E1: a novel lipid mediator in the resolution of allergic airway inflammation. Expert Rev Clin Immunol. 2008;4:669–72.

    CAS  PubMed  Article  Google Scholar 

  177. Bathina S, Gundala NKV, Rhenghachar P, Polavarapu S, Hari AD, Sadananda M, et al. Resolvin D1 ameliorates nicotinamide-streptozotocin-induced type 2 diabetes mellitus by its anti-inflammatory action and modulating PI3K/Akt/mTOR pathway in the brain. Arch Med Res. 2020;51:492–503.

    CAS  PubMed  Article  Google Scholar 

  178. Das UN. Ageing: Is there a role for arachidonic acid and other bioactive lipids? J Adv Res. 2018;11:67–79.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  179. Das UN. Bioactive lipids in age-related disorders. Adv Exp Med Biol. 2020;1260:33–83.

    CAS  PubMed  Article  Google Scholar 

  180. Gobbetti T, Ducheix S, le Faouder P, Perez T, Riols F, Boue J, et al. Protective effects of n-6 fatty acids-enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor. Br J Pharmacol. 2015;172:910–23.

    CAS  PubMed  Article  Google Scholar 

  181. Marcone S, Evans P, Fitzgerald DJ. 15-Deoxy-Δ12,14-prostaglandin J2 modifies components of the proteasome and inhibits inflammatory responses in human endothelial cells. Front Immunol. 2016;7:459.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  182. Park SW, Cho C, Cho BN, Kim Y, Goo TW, Kim YI. 15-deoxy-Δ12,14 -prostaglandin J 2 down-regulates activin-induced activin receptor, Smad, and cytokines expression via suppression of NF- κ B and MAPK signaling in HepG2 cells. PPAR Res. 2013;2013:751261.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  183. Ishino H, Kawahito Y, Tsubouchi Y, Kohno M, Wada M, Yamamoto A, et al. Feedback control of the arachidonate cascade in osteoblastic cells by 15-deoxy-delta-prostaglandin J(2). J Clin Biochem Nutr. 2008;42:64–69.

    CAS  PubMed  Article  Google Scholar 

  184. Faour WH, Mancini A, He QW, Di Battista JA. T-cell-derived interleukin-17 regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of the p38 mitogen-activated protein kinase cascade: role of distal sequences in the 3’-untranslated region of COX-2 mRNA. J Biol Chem. 2003;278:26897–907.

    CAS  PubMed  Article  Google Scholar 

  185. Stamp LK, Cleland LG, James MJ. Upregulation of synoviocyte COX-2 through interactions with T lymphocytes: role of interleukin 17 and tumor necrosis factor-alpha. J Rheumatol. 2004;31:1246–54.

    CAS  PubMed  Google Scholar 

  186. Stamp LK, James MJ, Cleland LG. Paracrine upregulation of monocyte cyclooxygenase-2 by mediators produced by T lymphocytes: role of interleukin 17 and interferon-gamma. J Rheumatol. 2004;31:1255–64.

    CAS  PubMed  Google Scholar 

  187. Das UN. Minerals, trace elements and vitamins interact with essential fatty acids and prostaglandins to prevent hypertension, thrombosis, hypercholesterolemia and atherosclerosis and their attendant complications. IRCS J Med Sci. 1985;13:684–7.

    CAS  Google Scholar 

  188. Das UN. Magnesium, essential fatty acids and cardiovascular diseases. J Assoc Physicians India. 1987;35:171.

    CAS  PubMed  Google Scholar 

  189. Das UN. Nutrients, essential fatty acids and prostaglandins interact to augment immune responses and prevent genetic damage and cancer. Nutrition. 1989;5:106–10.

    CAS  PubMed  Google Scholar 

  190. Das UN. Interaction(s) between nutrients, essential fatty acids, eicosanoids, free radicals, nitric oxide, anti-oxidants and endothelium and their relationship to human essential hypertension. Med Sci Res. 2000;28:75–83.

    Google Scholar 

  191. Das UN. Essential fatty acids: biochemistry. Physiol Pathol Biotechnol J. 2006;1:420–39.

    CAS  Google Scholar 

  192. Poorani R, Bhatt AN, Dwarakanath BS, Das UN. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance. Eur J Pharmacol. 2016;785:116–32.

    CAS  PubMed  Article  Google Scholar 

  193. LeBlanc CP, Fiset S, Surette ME, Turgeon O’Brien H, Rioux FM. Maternal iron deficiency alters essential fatty acid and eicosanoid metabolism and increases locomotion in adult guinea pig offspring. J Nutr. 2009;139:1653–9.

    CAS  PubMed  Article  Google Scholar 

  194. Bertrandt J, Klos A, Debski B. Content of polyunsaturated fatty acids (PUFAs) in serum and liver of rats fed restricted diets supplemented with vitamins B2, B6 and folic acid. Biofactors. 2004;22:189–92.

    CAS  PubMed  Article  Google Scholar 

  195. Srivastava KC. Ascorbic acid enhances the formation of prostaglandin E1 in washed human platelets and prostacyclin in rat aortic rings. Prostaglandins Leukot Med. 1985;18:227–33.

    CAS  PubMed  Article  Google Scholar 

  196. Das UN. Bioactive lipids as mediators of the beneficial actions of statins. J Cardiovasc Pharmacol. 2019;74:4–8.

    CAS  PubMed  Article  Google Scholar 

  197. Das UN. Essential fatty acids as possible mediators of the actions of statins. Prostaglandins Leukot Essent Fat Acids. 2001;65:37–40.

    CAS  Article  Google Scholar 

  198. Planagumà A, Pfeffer MA, Rubin G, Croze R, Uddin M, Serhan CN, et al. Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4. Mucosal Immunol. 2010;3:270–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  199. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Nishi SP, Martinez JD, et al. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation. 2006;114:929–35.

    CAS  PubMed  Article  Google Scholar 

  200. Wang H, Anthony D, Yatmaz S, Wijburg O, Satzke C, Levy B, et al. Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model. Clin Sci. 2017;131:2347–62.

    CAS  Article  Google Scholar 

  201. Ortiz-Muñoz G, Mallavia B, Bins A, Headley M, Krummel MF, Looney MR. Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood. 2014;124:2625–34.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  202. Chiang N, Serhan CN. New mechanism for an old drug: aspirin triggers anti-inflammatory lipid mediators with gender implications. Compr Ther. 2006;32:150–7.

    PubMed  Google Scholar 

  203. Chiang N, Bermudez EA, Ridker PM, Hurwitz S, Serhan CN. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci USA 2004;101:15178–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  204. Chan MM-Y, Moore AR. Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production. J Immunol. 2010;184:6418–26.

    CAS  PubMed  Article  Google Scholar 

  205. Zhang Y, Desai A, Yang SY, Bae KB, Antczak MI, Fink SP, et al. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science. 2015;348:1223 https://doi.org/10.1126/science.aaa2340.

    CAS  Article  Google Scholar 

  206. North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447:1007–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  207. Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, et al. Apoptotic cells activate the “Phoenix Rising” pathway to promote wound healing and tissue regeneration. Sci Signal;3:ra13. https://doi.org/10.1126/scisignal.2000634.

  208. Hoggatt J, Mohammad KS, Singh P, Hoggatt AF, Chitteti BR, Speth JM, et al. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature. 2013;495:365–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  209. Diaz MF, Li N, Lee HJ, Evans SM, Willey HE, Arora N, et al. Biomechanical forces promote blood development through prostaglandin E2 and the cAMP–PKA signaling axis. J Exp Med. 2015;212:665–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  210. Fang X, Abbott J, Cheng L, Colby JK, Lee JW, Levy BD, et al. Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4. J Immunol. 2015;195:875–81.

    CAS  PubMed  Article  Google Scholar 

  211. Cheng X, He S, Yuan J, Miao S, Gao H, Zhang J, et al. Lipoxin A4 attenuates LPS-induced mouse acute lung injury via Nrf2-mediated E-cadherin expression in airway epithelial cells. Free Radic Biol Med. 2016;93:52–66.

    CAS  PubMed  Article  Google Scholar 

  212. Bai Y, Wang J, He Z, Yang M, Li L, Jiang H. Mesenchymal stem cells reverse diabetic nephropathy disease via lipoxin A4 by targeting transforming growth factor β (TGF-β)/smad pathway and pro-Inflammatory cytokines. Med Sci Monit. 2019;25:3069–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  213. Das UN. Ageing, telomere, stem cells biology and inflammation and their relationship to polyunsaturated fatty acids. Agro Food Ind Hi Tech. 2015;26:38–41.

    Google Scholar 

  214. Das UN. Essential fatty acids and their metabolites as modulators of stem cell biology with reference to inflammation, cancer and metastasis. Cancer Metastasis Rev. 2011;30:311–24.

    CAS  PubMed  Article  Google Scholar 

  215. Romano M, Patruno S, Pomilio A, Recchiuti A. Proresolving lipid mediators and receptors in stem cell biology: concise review. Stem Cells Transl Med. 2019;8:992–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  216. Zhang G, Liu X, Wang C, Qu L, Deng J, Wang H, et al. Resolution of PMA-induced skin inflammation involves interaction of IFN-γ and ALOX15. Mediators Inflamm. 2013;2013:930124.

    PubMed  PubMed Central  Google Scholar 

  217. Shryock N, McBerry C, Salazar Gonzalez RM, Janes S, Costa FT, Aliberti J. Lipoxin A4 and 15-epi-lipoxin A4 protect against experimental cerebral malaria by inhibiting IL-12/IFN-γ in the brain. PLoS ONE. 2013;8:e61882.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  218. Wang C, Xiao M, Liu X, Ni C, Liu J, Erben U, et al. IFN-γ-mediated downregulation of LXA4 is necessary for the maintenance of nonresolving inflammation and papilloma persistence. Cancer Res. 2013;73:1742–51.

    CAS  PubMed  Article  Google Scholar 

  219. Ohse T, Ota T, Kieran N, Godson C, Yamada K, Tanaka T, et al. Modulation of interferon-induced genes by lipoxin analogue in anti-glomerular basement membrane nephritis. J Am Soc Nephrol. 2004;15:919–27.

    CAS  PubMed  Article  Google Scholar 

  220. Börgeson E, Docherty NG, Murphy M, Rodgers K, Ryan A, O’Sullivan TP, et al. Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. FASEB J. 2011;25:2967–79.

    PubMed  Article  CAS  Google Scholar 

  221. Wei J, Mattapallil MJ, Horai R, Jittayasothorn Y, Modi AP, Sen HN, et al. A novel role for lipoxin A4 in driving a lymph node-eye axis that controls autoimmunity to the neuroretina. Elife. 2020;9:e51102.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  222. Rossi S, Di Filippo C, Gesualdo C, Testa F, Trotta MC, Maisto R, et al. Interplay between intravitreal RvD1 and local endogenous sirtuin-1 in the protection from endotoxin-induced uveitis in rats. Mediators Inflamm. 2015;2015:126408.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Medeiros R, Rodrigues GB, Figueiredo CP, Rodrigues EB, Grumman A Jr, Menezes-de-Lima O Jr, et al. Molecular mechanisms of topical anti-inflammatory effects of lipoxin A(4) in endotoxin-induced uveitis. Mol Pharmacol. 2008;74:154–61.

    CAS  PubMed  Article  Google Scholar 

  224. Suzuki M, Noda K, Kubota S, Hirasawa M, Ozawa Y, Tsubota K, et al. Eicosapentaenoic acid suppresses ocular inflammation in endotoxin-induced uveitis. Mol Vis. 2010;16:1382–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Shoda H, Yanai R, Yoshimura T, Nagai T, Kimura K, Sobrin L, et al. Dietary omega-3 fatty acids suppress experimental autoimmune uveitis in association with inhibition of Th1 and Th17 cell function. PLoS ONE. 2015;10:e0138241.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  226. Tateishi N, Kakutani S, Kawashima H, Shibata H, Morita I. Dietary supplementation of arachidonic acid increases arachidonic acid and lipoxin A4 contents in colon but does not affect severity or prostaglandin E2 content in murine colitis model. Lipids Health Dis. 2014;13:30.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  227. Tateishi N, Kaneda Y, Kakutani S, Kawashima H, Shibata H, Morita I. Dietary supplementation with arachidonic acid increases arachidonic acid content in paw, but does not affect arthritis severity or prostaglandin E2 content in rat adjuvant-induced arthritis model. Lipids Health Dis. 2015;14:3.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  228. Cheng T, Ding S, Liu S, Li X, Tang X, Sun L. Resolvin D1 Improves the Treg/Th17 imbalance in systemic lupus erythematosus through miR-30e-5p. Front Immunol. 2021;12:668760.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  229. Navarini L, Bisogno T, Margiotta DPE, Piccoli A, Angeletti S, Laudisio A, et al. Role of the specialized proresolving mediator resolvin D1 in systemic lupus erythematosus: preliminary results. J Immunol Res. 2018;2018:5264195.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  230. Li J, Sun Q, Zheng C, Bai C, Liu C, Zhao X, et al. Lipoxin A4-mediated p38 MAPK signaling pathway protects mice against collagen-induced arthritis. Biochem Genet. 2021;59:346–65.

    CAS  PubMed  Article  Google Scholar 

  231. Conte FP, Menezes-de-Lima O Jr, Verri WA Jr, Cunha FQ, Penido C, Henriques MG. Lipoxin A(4) attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects. Br J Pharmacol. 2010;161:911–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  232. Chan MM, Moore AR. Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production. J Immunol. 2010;184:6418–26.

    CAS  PubMed  Article  Google Scholar 

  233. Thomas E, Leroux JL, Blotman F, Chavis C. Conversion of endogenous arachidonic acid to 5,15-diHETE and lipoxins by polymorphonuclear cells from patients with rheumatoid arthritis. Inflamm Res. 1995;44:121–4.

    CAS  PubMed  Article  Google Scholar 

  234. Özgül Özdemir RB, Soysal Gündüz Ö, Özdemir AT, Akgül Ö. Low levels of pro-resolving lipid mediators lipoxin-A4, resolvin-D1 and resolvin-E1 in patients with rheumatoid arthritis. Immunol Lett. 2020;227:34–40.

    PubMed  Article  CAS  Google Scholar 

  235. Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. 1984;5:25–44.

    CAS  PubMed  Article  Google Scholar 

  236. Walev I, Klein J, Husmann M, Valeva A, Strauch S, Wirtz H, et al. Potassium regulates IL-1 beta processing via calcium-independent phospholipase A2. J Immunol. 2000;164:5120–4.

    CAS  PubMed  Article  Google Scholar 

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Das, U.N. Pro- and anti-inflammatory bioactive lipids imbalance contributes to the pathobiology of autoimmune diseases. Eur J Clin Nutr (2022). https://doi.org/10.1038/s41430-022-01173-8

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