Role of cytokines and platelet-activating factor in inflammatory bowel disease

Implications for therapy

Abstract

BACKGROUND: Platelet-activating factor (PAF) and cytokines, such as interleukins, tumor necrosis factor, and others, are thought to play a role in the inflammatory process involving gastrointestinal disorders such as Crohn's disease, ulcerative colitis, ischemic colitis, or antibiotic-associated colitis. PURPOSE: This study was undertaken to review the latest literature on the role of PAF and cytokines in the genesis of inflammatory bowel disease and implications for therapy and management. RESULTS: PAF is an endogenous phospholipid involved in hypersensitivity and inflammatory reactions such as platelet and neutrophil aggregation, vasodilation, increased vascular permeability, and leukocyte adhesion, which have been associated with inflammatory processes. Cytokines are peptides that regulate and coordinate inflammatory and immunologic responses. Increased production of cytokines has been reported during Crohn's disease and ulcerative colitis and is correlated with disease activity. CONCLUSIONS: Because PAF and cytokines may have an important role in the pathogenesis of inflammatory bowel disease, their inhibition by specific antagonists, mediators, or other agents such as steroids may have a potential therapeutic benefit in treatment and management of these inflammatory diseases in the near future.

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References

  1. 1.

    Campbell CA, Walker-Smith JA, Hindocha P, Adinolfi M. Acute phase proteins in chronic inflammatory bowel disease in childhood. J Pediatr Gastroenterol Nutr 1982;1:193–200.

    PubMed  Google Scholar 

  2. 2.

    Chambers RE, Stross P, Barry RE, Whicher JT. Serum amyloid A protein compared with C-reactive protein, alpha 1-antitrypsin and alpha 1-acid glycoprotein as a monitor of inflammatory bowel disease. Eur J Clin Invest 1987;17:460–7.

    PubMed  Google Scholar 

  3. 3.

    Prantera C, Davoli M, Lorenzetti R,et al. Clinical and laboratory indicators of extent of ulcerative colitis: serum C-reactive protein helps the most. J Clin Gastroenterol 1988;10:41–5.

    PubMed  Google Scholar 

  4. 4.

    Pinckard RN, Ludwig JC, McManus LM. Platelet-activating factors. In: Gallin JI, Goldstein IM, Synderman R, eds. Inflammation: Basic principles and clinical correlates. New York: Raven Press, 1988:139–67.

    Google Scholar 

  5. 5.

    Brynskov J, Nielsen OH, Ahnfelt-Ronne I, Bendtzen K. Cytokines in inflammatory bowel disease. Scand J Gastroenterol 1992;27:897–906.

    PubMed  Google Scholar 

  6. 6.

    Stadnyk AW. Cytokine production by epithelial cells. FASEB J 1994;8:1041–7.

    PubMed  Google Scholar 

  7. 7.

    Radema SA, Van Deventer SJ, Cerami A. Interleukin 1β is expressed predominantly by enterocytes in experimental colitis. Gastroenterology 1991;100:1180–6.

    PubMed  Google Scholar 

  8. 8.

    Jones SC, Trejdosiewicz LK, Banks RE,et al. Expression of interleukin-6 by intestinal enterocytes. J Clin Pathol 1993;46:1097–100.

    PubMed  Google Scholar 

  9. 9.

    Dinarello CA. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 1984;311:1413–8.

    PubMed  Google Scholar 

  10. 10.

    Fey GH, Gauldie J. The acute phase response of the liver in inflammation. Prog Liver Dis 1990;9:89–116.

    PubMed  Google Scholar 

  11. 11.

    Filkins JP. Cytokines: mediators of the septic syndrome and septic shock. In: Taylor RW, Shoemaker WC, eds. Critical care: state of the art. Vol. 12. Fullerton, CA: Society of Critical Care Medicine, 1991:351–71.

    Google Scholar 

  12. 12.

    Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982;389:39–48.

    PubMed  Google Scholar 

  13. 13.

    Prescott SM, Zimmerman GA, McIntyre TM. Platelet-activating factor. J Biol Chem 1990;265:17381–4.

    PubMed  Google Scholar 

  14. 14.

    Benveniste J. Platelet activating factor, a new mediator of anaphylaxis from rabbit and human basophils. Nature 1974;249:581–4.

    PubMed  Google Scholar 

  15. 15.

    Chignard M, Le Couedic JP, Tence M, Vargaftig BB, Benveniste J. The role of PAF in platelet aggregation. Nature 1979;279:779–880.

    Google Scholar 

  16. 16.

    Doebber JW, Wu MS, Shen TY. Platelet activating factor intravenous infusion in rat stimulates vascular lysosomal hydrolase secretion independent of blood neutrophils. Biochem Biophys Res Commun 1984;125:980–7.

    PubMed  Google Scholar 

  17. 17.

    Humphrey DM, McManus LM, Satouchi K, Hanahan DJ, Pinckard RN. Vasoactive properties of acetyl glyceryl ether phosphorylcholine and analogues. Lab Invest 1982;46:422–7.

    PubMed  Google Scholar 

  18. 18.

    McManus LM, Hanahan DJ, Demopoulos CA, Pinckard RN. Pathobiology of the intravenous infusion of acetyl glyceryl ether phosphorylcholine (AGEPC), a synthetic platelet activating factor (PAF), in the rabbit. J Immunol 1980;124:2919–24.

    PubMed  Google Scholar 

  19. 19.

    Poitevin B, Mencia-Huerta JM, Roubin R, Benveniste J. Role of PAF acether (platelet activating factor) in neutrophil activation. In: Said SI, ed. Pulmonary circulation and acute lung injury. New York: Furtura Publishing, 1985:357–73.

    Google Scholar 

  20. 20.

    Camussi G, Brentjens J, Bussolino F, Tetta C. Role of platelet activating factor in immunopathological reactions. In: Otterness I, ed. Inflammation research. Vol. 11. New York: Raven Press, 1986:92–108.

    Google Scholar 

  21. 21.

    Tagesson C, Lindahl M, Otamiri T. BN 52021 ameliorates mucosal damage associated with small intestinal ischemia in rats. In: Braquet P, ed. Ginkgolides: chemistry, biology, pharmacology and clinical science. Barcelona: Prous Science Publishers, 1988:553–61.

    Google Scholar 

  22. 22.

    Wallace JL, Steel G, Whittle B, Lagente V, Vargaftig BB. Evidence for platelet-activating factor as a mediator of endotoxin-induced gastrointestinal damage in the rat. Gastroenterology 1983;93:765–73.

    Google Scholar 

  23. 23.

    Rosam AC, Wallace JL, Whittle B. Potent ulcerogenic actions of platelet-activating factor on the stomach. Nature 1986;319:54–6.

    PubMed  Google Scholar 

  24. 24.

    Wallace JL. Release of platelet-activating factor (PAF) and accelerated healing induced by a PAF antagonist in an animal model of chronic colitis. Can J Physiol Pharmacol 1988;66:422–5.

    PubMed  Google Scholar 

  25. 25.

    Eliakim R, Karmeli F, Razin E, Rachmilewitz D. Role of platelet activating factor in ulcerative colitis. Gastroenterology 1988;95:1167–72.

    PubMed  Google Scholar 

  26. 26.

    Denizot Y, Chaussade S, Nathan N. PAF-acether and acetylhydrolase in stool of patients with Crohn's Disease. Dig Dis Sci 1992;37:432–7.

    PubMed  Google Scholar 

  27. 27.

    Rachmilewitz D, Eliakim R, Simon P, Ligumsky M, Karmeli F. Cytokines and platelet-activating factor in human inflamed colonic mucosa. Agents Actions 1992; Spec No:C32-6.

  28. 28.

    Sobhani I, Hochlaf S, Denizot Y,et al. Raised concentrations of platelet-activating factor in colonic mucosa of Crohn's disease patients. Gut 1992;33:1220–5.

    PubMed  Google Scholar 

  29. 29.

    Sharon P, Ligumsky D, Rachmilewitz D, Zor U. Role of prostaglandins in ulcerative colitis: enhanced production during active disease and inhibition by sulphasalazine. Gastroenterology 1978;75:638–40.

    PubMed  Google Scholar 

  30. 30.

    Hawkey CJ, Truelove SC. Effect of prednisolone on prostaglandins synthesis by rectal mucosa in ulcerative colitis. Gut 1981;22:190–3.

    PubMed  Google Scholar 

  31. 31.

    Hawkey CJ, Truelove SC. Inhibition of prostaglandin synthetase in human rectal mucosa. Gut 24;1983:213–7.

    PubMed  Google Scholar 

  32. 32.

    Hawkey CJ, Karmeli F, Rachmilewitz D. Imbalance of prostacyclin and thromboxane synthesis in Crohn's Disease. Gut 1983;24:881–5.

    PubMed  Google Scholar 

  33. 33.

    Boughton-Smith NK, Hawkey CJ, Whittle B. Biosynthesis of lipoxygenase and cyclooxygenase products from (14C) arachidonic acid by human colonic mucosa. Gut 1983;24:1176–82.

    PubMed  Google Scholar 

  34. 34.

    Lobos EA, Sharon P, Stenson WF. Chemotactic activity in inflammatory bowel disease: role of leukotriene B4. Dig Dis Sci 1987;32:1380–8.

    PubMed  Google Scholar 

  35. 35.

    Olaison G, Sjodahl R, Tagesson C. Increased phospholipase A2 activity of ileal mucosa in Crohn's disease. Digestion 1988;41:136–41.

    PubMed  Google Scholar 

  36. 36.

    Olaison G, Sjodahl R, Tagesson C. Increase in permeability and phospholipase A2 activity of colonic mucosa in Crohn's colitis. Digestion 1989;43:228–33.

    PubMed  Google Scholar 

  37. 37.

    Donowitz M. Arachidonic acid metabolites and their role in inflammatory bowel disease: an update requiring addition of a pathway. Gastroenterology 1985;88:580–7.

    PubMed  Google Scholar 

  38. 38.

    Braquet P, Vargaftig BB. Pharmacology of platelet activating factor. Transplant Proc 1986;28:10–9.

    Google Scholar 

  39. 39.

    Tagesson C, Franzen L, Dahl G, Westrom B. Lysophosphatidylcholine increases rat ileal permeability to macromolecules. Gut 1985;26:369–77.

    PubMed  Google Scholar 

  40. 40.

    Rachmilewitz D, Simon PL, Schwartz LW, Griswold DE, Fondacaro JD, Wasserman MA. Inflammatory mediators of experimental colitis in rats. Gastroenterology 1989;97:326–37.

    PubMed  Google Scholar 

  41. 41.

    Rachmilewitz D, Simon PL, Sjogrn R, Fondacaro JD, Wasserman MA, Bodecker E. Interleukin-1: a sensitive maker of colonic inflammation. Gastroenterology 1989;94:A363.

    Google Scholar 

  42. 42.

    Mahida YR, Jones PD, Daneshmend TK, Hawkey CJ. Peptide regulatory factors in the gut. Recent Adv Gastroenterology 1990;8:61–80.

    Google Scholar 

  43. 43.

    Durum SK, Schmidt JA, Oppenheim JJ. Interleukin 1: an immunological perspective. Annu Rev Immunol 1985;3:263–87.

    PubMed  Google Scholar 

  44. 44.

    Elner VM, Streiter RM, Elner SG, Baggiolini M, Lindley I, Kunkel SL. Neutrophil chemotactic factor (IL8) gene expression by cytokine-treated retinal pigment epithelial cells. Am J Pathol 1990;136:745–50.

    PubMed  Google Scholar 

  45. 45.

    Mahida YR, Lamming CE, Gallagher A, Hawthorne AB, Hawkey CJ. 5-Aminosalicylic acid is a potent inhibitor of IL1B production in organ culture of colonic biopsies form patients with inflammatory bowel disease. Gut 1991;32:50–4.

    PubMed  Google Scholar 

  46. 46.

    Izzo RS, Witkon K, Chen AI, Hadjiyane C, Weinstein M, Pellecchia C. Neutrophil-activating peptide (interleukin-8) in colonic mucosa from patients with Crohn's disease. Scand J Gastroenterol 1993;28:296–300.

    PubMed  Google Scholar 

  47. 47.

    Satsangi J, Wolstencroft RA, Cason J, Ainley CC, Dumonde CC, Thompson RP. Interleukin 1 in Crohn's disease. Clin Exp Immunol 1987;67:594–605.

    PubMed  Google Scholar 

  48. 48.

    Mazlam MZ, Hodgson HJ. Peripheral blood monocyte cytokine production and acute phase response in inflammatory bowel disease. Gut 1992;33:773–8.

    PubMed  Google Scholar 

  49. 49.

    Reinecker HC, Steffen M, Witthoeft T,et al. Enhanced secretion of tumor 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 1993;94:174–81.

    PubMed  Google Scholar 

  50. 50.

    Mitsuyama K, Sasaki E, Toyonaga A,et al. Colonic mucosal interleukin-6 in inflammatory bowel disease. Digestion 1991;50:104–11.

    PubMed  Google Scholar 

  51. 51.

    Mazlam MZ, Hodgson HJ. Interrelations between interleukin-6, interleukin-1 beta, plasma C-reactive protein values, andin vitro C-reactive protein generation in patients with inflammatory bowel disease. Gut 1994;35:77–83.

    PubMed  Google Scholar 

  52. 52.

    Raab Y, Hallgren R, Gerdin B. Enhanced intestinal synthesis of interleukin-6 is related to the disease severity and activity in ulcerative colitis. Digestion 1994;55:44–9.

    PubMed  Google Scholar 

  53. 53.

    Jones SC, Crabtree JE, Rembacken BJ,et al. Mucosal interleukin-6 secretion in ulcerative colitis: effects of anti-inflammatory drugs and T-cell stimulation. Scand J Gastroenterol 1994;29:722–8.

    PubMed  Google Scholar 

  54. 54.

    Sher ME, D'Angelo AJ, Stein TA, Bailey B, Burns G, Wise L. Cytokines in Crohn's colitis. Am J Surg 1995;169:133–6.

    PubMed  Google Scholar 

  55. 55.

    Mahida YR, Ceska M, Effenberger F, Kurlak L, Lindley I, Hawkey CJ. Enhanced synthesis of neutrophil-activating peptide-1/interleukin-8 in active ulcerative colitis. Clin Sci 1992;82:273–5.

    PubMed  Google Scholar 

  56. 56.

    Izzo RS, Witkon K, Chen AI, Hadjiyane C, Weinstein MI, Pellecchia C. Interleukin-8 and neutrophil markers in colonic mucosa from patients with ulcerative colitis. Am J Gastroenterol 1992;87:1447–52.

    PubMed  Google Scholar 

  57. 57.

    Mitsuyama K, Toyonaga A, Sasaki E,et al. IL-8 as an important chemoattractant for neutrophils in ulcerative colitis and Crohn's disease. Clin Exp Immunol 1994;96:432–6.

    PubMed  Google Scholar 

  58. 58.

    Mazzucchelli L, Hauser C, Zgraggen K,et al. Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation. Am J Pathol 1994;144:997–1007.

    PubMed  Google Scholar 

  59. 59.

    Mahida YR, Kurlak L, Hawkey CJ. Circulating and tissue interleukin 2 receptor levels in inflammatory bowel disease. Clin Exp Immunol 1990;82:75–80.

    PubMed  Google Scholar 

  60. 60.

    Youngman KR, Simon PL, West GA,et al. Localization of intestinal interleukin 1 activity and protein and gene expression to lamina propria cells. Gastroenterology 1993;104:749–58.

    PubMed  Google Scholar 

  61. 61.

    McCabe RP, Secrist H, Botney M, Egan M, Peters MG. Cytokine mRNA expression in intestine from normal and inflammatory bowel disease patients. Clin Immunol Immunopathol 1993;66:52–8.

    PubMed  Google Scholar 

  62. 62.

    Gahring LC, Buckley A, Daynes RA. Presence of epidermal-derived thymocyte activating factor/interleukin 1 in normal human stratum corneum. J Clin Invest 1985;76:1585–91.

    PubMed  Google Scholar 

  63. 63.

    Hauser C, Saurat JH, Schmitt A, Jaunin F, Dayer JM. Interleukin 1 is present in normal human epidermis. J Immunol 1986;136:3317–23.

    PubMed  Google Scholar 

  64. 64.

    Kirnbauer R, Köck A, Schwarz T,et al. IFN-β2, B-cell differentiation factor 2, or hybridoma growth factor (IL-6) is expressed and released by human epidermal cells and epidermoid carcinoma cell lines. J Immunol 1989;142:1922–8.

    PubMed  Google Scholar 

  65. 65.

    Köck A, Schwarz T, Kirnbauer R,et al. Human keratinocytes are a source for tumor necrosis factorα: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 1990;172:1609–14.

    PubMed  Google Scholar 

  66. 66.

    Reinecker HC, Loh EY, Ringler DJ, Mehta A, Rombeau JL, MacDermott RP. Monocyte-chemoattractant protein 1 gene expression in intestinal epithelial cells and inflammatory bowel disease mucosa. Gastroenterology 1995;108:40–50.

    PubMed  Google Scholar 

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Correspondence to Walter E. Longo M.D..

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Nassif, A., Longo, W.E., Mazuski, J.E. et al. Role of cytokines and platelet-activating factor in inflammatory bowel disease. Dis Colon Rectum 39, 217–223 (1996). https://doi.org/10.1007/BF02068079

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Key words

  • Platelet-activating factor (PAF)
  • Cytokines
  • Inflammatory bowel disease