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J Clin Invest. Sep 1990; 86(3): 972–980.
PMCID: PMC296817

Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis.

Abstract

Interleukin 1 (IL-1) may be a key mediator of inflammation and tissue damage in inflammatory bowel disease (IBD). In rabbits with immune complex-induced colitis, IL-1 alpha and beta mRNA levels were detectable at 4 h, peaked at 12 but were absent at 96 h after the induction of colitis. Colonic IL-1 tissue levels were measured by specific radioimmunoassays. IL-1 alpha was significantly elevated at 4 h (9.4 +/- 1.5 ng/g colon), progressively increased at 48 h (31 +/- 5.8 ng/g) and then decreased by 96 h (11.5 +/- 3.4 ng/g). IL-1 beta levels were 2.0 +/- 0.5 ng/g colon at 4 h, 5.0 +/- 1.6 ng/g at 48 h and undetectable by 96 h. By comparison, colonic levels of PGE2 and LTB4 were unchanged during the first 12 h and did not become elevated until 24 h. IL-1 alpha levels were highly correlated with inflammation (r = 0.885, P less than 0.0001), edema (r = 0.789, P less than 0.0001) and necrosis (r = 0.752, P less than 0.0005). Treatment with a specific IL-1 receptor antagonist (IL-1 ra) before and during the first 33 h after the administration of immune complexes markedly reduced inflammatory cell infiltration index (from 3.2 +/- 0.4 to 1.4 +/- 0.3, P less than 0.02), edema (from 2.2 +/- 0.4 to 0.6 +/- 0.3, P less than 0.01) and necrosis (from 43 +/- 10% to 6.6 +/- 3.2%, P less than 0.03) compared to vehicle-matched colitis animals. These studies demonstrate that (a) IL-1 gene expression and synthesis occur early in the course of immune complex-induced colitis; (b) are significantly elevated for 12 h before the appearance of PGE2 and LTB4; (c) tissue levels of IL-1 correlate with the degree of tissue inflammation and; (d) specific blockade of IL-1 receptors reduces the inflammatory responses associated with experimental colitis.

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Selected References

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  • Dinarello CA. Interleukin-1 and its biologically related cytokines. Adv Immunol. 1989;44:153–205. [PubMed]
  • Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7907–7911. [PMC free article] [PubMed]
  • Lomedico PT, Gubler U, Hellmann CP, Dukovich M, Giri JG, Pan YC, Collier K, Semionow R, Chua AO, Mizel SB. Cloning and expression of murine interleukin-1 cDNA in Escherichia coli. Nature. 312(5993):458–462. [PubMed]
  • Endres S, Cannon JG, Ghorbani R, Dempsey RA, Sisson SD, Lonnemann G, Van der Meer JW, Wolff SM, Dinarello CA. In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation. Eur J Immunol. 1989 Dec;19(12):2327–2333. [PubMed]
  • Neta R, Oppenheim JJ. Why should internists be interested in interleukin-1? Ann Intern Med. 1988 Jul 1;109(1):1–3. [PubMed]
  • O'Garra A. Interleukins and the immune system 1. Lancet. 1989 Apr 29;1(8644):943–947. [PubMed]
  • Fontana A, Hengartner H, Weber E, Fehr K, Grob PJ, Cohen G. Interleukin 1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int. 1982;2(2):49–53. [PubMed]
  • Wood DD, Ihrie EJ, Dinarello CA, Cohen PL. Isolation of an interleukin-1-like factor from human joint effusions. Arthritis Rheum. 1983 Aug;26(8):975–983. [PubMed]
  • Eastgate JA, Symons JA, Wood NC, Grinlinton FM, di Giovine FS, Duff GW. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet. 1988 Sep 24;2(8613):706–709. [PubMed]
  • The effect of diltiazem on mortality and reinfarction after myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group. N Engl J Med. 1988 Aug 18;319(7):385–392. [PubMed]
  • Cannon JG, Tompkins RG, Gelfand JA, Michie HR, Stanford GG, van der Meer JW, Endres S, Lonnemann G, Corsetti J, Chernow B, et al. Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis. 1990 Jan;161(1):79–84. [PubMed]
  • Shore A, Jaglal S, Keystone EC. Enhanced interleukin 1 generation by monocytes in vitro is temporally linked to an early event in the onset or exacerbation of rheumatoid arthritis. Clin Exp Immunol. 1986 Aug;65(2):293–302. [PMC free article] [PubMed]
  • Satsangi J, Wolstencroft RA, Cason J, Ainley CC, Dumonde DC, Thompson RP. Interleukin 1 in Crohn's disease. Clin Exp Immunol. 1987 Mar;67(3):594–605. [PMC free article] [PubMed]
  • Movat HZ, Cybulsky MI, Colditz IG, Chan MK, Dinarello CA. Acute inflammation in gram-negative infection: endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc. 1987 Jan;46(1):97–104. [PubMed]
  • Raz A, Wyche A, Siegel N, Needleman P. Regulation of fibroblast cyclooxygenase synthesis by interleukin-1. J Biol Chem. 1988 Feb 25;263(6):3022–3028. [PubMed]
  • Cominelli F, Nast CC, Dinarello CA, Gentilini P, Zipser RD. Regulation of eicosanoid production in rabbit colon by interleukin-1. Gastroenterology. 1989 Dec;97(6):1400–1405. [PubMed]
  • Zipser RD, Nast CC, Lee M, Kao HW, Duke R. In vivo production of leukotriene B4 and leukotriene C4 in rabbit colitis. Relationship to inflammation. Gastroenterology. 1987 Jan;92(1):33–39. [PubMed]
  • Brown JA, Zipser RD. Prostaglandin regulation of colonic blood flow in rabbit colitis. Gastroenterology. 1987 Jan;92(1):54–59. [PubMed]
  • Schumert R, Nast CC, Cominelli F, Zipser RD. Effects of 16,16-dimethyl prostaglandin E2 and indomethacin on leukotriene B4 and inflammation in rabbit colitis. Prostaglandins. 1988 Oct;36(4):565–577. [PubMed]
  • Cannon JG, Clark BD, Wingfield P, Schmeissner U, Losberger C, Dinarello CA, Shaw AR. Rabbit IL-1. Cloning, expression, biologic properties, and transcription during endotoxemia. J Immunol. 1989 Apr 1;142(7):2299–2306. [PubMed]
  • Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. [PubMed]
  • Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. [PubMed]
  • KIRSNER JB, ELCHLEPP J. The production of an experimental ulcerative colitis in rabbits. Trans Assoc Am Physicians. 1957;70:102–119. [PubMed]
  • Hodgson HJ, Potter BJ, Skinner J, Jewell DP. Immune-complex mediated colitis in rabbits. An experimental model. Gut. 1978 Mar;19(3):225–232. [PMC free article] [PubMed]
  • Arend WP, Welgus HG, Thompson RC, Eisenberg SP. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990 May;85(5):1694–1697. [PMC free article] [PubMed]
  • Zipser RD, Patterson JB, Kao HW, Hauser CJ, Locke R. Hypersensitive prostaglandin and thromboxane response to hormones in rabbit colitis. Am J Physiol. 1985 Oct;249(4 Pt 1):G457–G463. [PubMed]
  • Zipser RD, Patterson JB, Leduc LE. Chemotactic peptide stimulation of leukotrienes from healthy and inflamed rabbit colons. J Pharmacol Exp Ther. 1987 Apr;241(1):218–222. [PubMed]
  • Rachmilewitz D, Simon PL, Schwartz LW, Griswold DE, Fondacaro JD, Wasserman MA. Inflammatory mediators of experimental colitis in rats. Gastroenterology. 1989 Aug;97(2):326–337. [PubMed]
  • Yoshimura T, Matsushima K, Oppenheim JJ, Leonard EJ. Neutrophil chemotactic factor produced by lipopolysaccharide (LPS)-stimulated human blood mononuclear leukocytes: partial characterization and separation from interleukin 1 (IL 1). J Immunol. 1987 Aug 1;139(3):788–793. [PubMed]
  • Peveri P, Walz A, Dewald B, Baggiolini M. A novel neutrophil-activating factor produced by human mononuclear phagocytes. J Exp Med. 1988 May 1;167(5):1547–1559. [PMC free article] [PubMed]
  • Strieter RM, Kunkel SL, Showell HJ, Remick DG, Phan SH, Ward PA, Marks RM. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science. 1989 Mar 17;243(4897):1467–1469. [PubMed]
  • Matsushima K, Morishita K, Yoshimura T, Lavu S, Kobayashi Y, Lew W, Appella E, Kung HF, Leonard EJ, Oppenheim JJ. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med. 1988 Jun 1;167(6):1883–1893. [PMC free article] [PubMed]
  • Demczuk S, Baumberger C, Mach B, Dayer JM. Expression of human IL 1 alpha and beta messenger RNAs and IL 1 activity in human peripheral blood mononuclear cells. J Mol Cell Immunol. 1987;3(5):255–265. [PubMed]
  • Lonnemann G, Endres S, Van der Meer JW, Cannon JG, Koch KM, Dinarello CA. Differences in the synthesis and kinetics of release of interleukin 1 alpha, interleukin 1 beta and tumor necrosis factor from human mononuclear cells. Eur J Immunol. 1989 Sep;19(9):1531–1536. [PubMed]
  • Endres S, Ghorbani R, Lonnemann G, van der Meer JW, Dinarello CA. Measurement of immunoreactive interleukin-1 beta from human mononuclear cells: optimization of recovery, intrasubject consistency, and comparison with interleukin-1 alpha and tumor necrosis factor. Clin Immunol Immunopathol. 1988 Dec;49(3):424–438. [PubMed]
  • Kupper TS, Ballard DW, Chua AO, McGuire JS, Flood PM, Horowitz MC, Langdon R, Lightfoot L, Gubler U. Human keratinocytes contain mRNA indistinguishable from monocyte interleukin 1 alpha and beta mRNA. Keratinocyte epidermal cell-derived thymocyte-activating factor is identical to interleukin 1. J Exp Med. 1986 Dec 1;164(6):2095–2100. [PMC free article] [PubMed]
  • Cominelli F, Nast CC, Llerena R, Dinarello CA, Zipser RD. Interleukin 1 suppresses inflammation in rabbit colitis. Mediation by endogenous prostaglandins. J Clin Invest. 1990 Feb;85(2):582–586. [PMC free article] [PubMed]
  • Chang J, Gilman SC, Lewis AJ. Interleukin 1 activates phospholipase A2 in rabbit chondrocytes: a possible signal for IL 1 action. J Immunol. 1986 Feb 15;136(4):1283–1287. [PubMed]
  • Knudsen PJ, Dinarello CA, Strom TB. Prostaglandins posttranscriptionally inhibit monocyte expression of interleukin 1 activity by increasing intracellular cyclic adenosine monophosphate. J Immunol. 1986 Nov 15;137(10):3189–3194. [PubMed]
  • Dinarello CA, Dempsey RA, Allegretta M, LoPreste G, Dainiak N, Parkinson DR, Mier JW. Inhibitory effects of elevated temperature on human cytokine production and natural killer activity. Cancer Res. 1986 Dec;46(12 Pt 1):6236–6241. [PubMed]
  • Ham EA, Soderman DD, Zanetti ME, Dougherty HW, McCauley E, Kuehl FA., Jr Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4349–4353. [PMC free article] [PubMed]
  • Goodwin JS, Ceuppens J. Regulation of the immune response by prostaglandins. J Clin Immunol. 1983 Oct;3(4):295–315. [PubMed]
  • Strieter RM, Phan SH, Showell HJ, Remick DG, Lynch JP, Genord M, Raiford C, Eskandari M, Marks RM, Kunkel SL. Monokine-induced neutrophil chemotactic factor gene expression in human fibroblasts. J Biol Chem. 1989 Jun 25;264(18):10621–10626. [PubMed]
  • Larsen CG, Zachariae CO, Oppenheim JJ, Matsushima K. Production of monocyte chemotactic and activating factor (MCAF) by human dermal fibroblasts in response to interleukin 1 or tumor necrosis factor. Biochem Biophys Res Commun. 1989 May 15;160(3):1403–1408. [PubMed]
  • Zucali JR, Dinarello CA, Oblon DJ, Gross MA, Anderson L, Weiner RS. Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2. J Clin Invest. 1986 Jun;77(6):1857–1863. [PMC free article] [PubMed]
  • Baggiolini M, Walz A, Kunkel SL. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest. 1989 Oct;84(4):1045–1049. [PMC free article] [PubMed]
  • Weisbart RH, Golde DW, Clark SC, Wong GG, Gasson JC. Human granulocyte-macrophage colony-stimulating factor is a neutrophil activator. Nature. 314(6009):361–363. [PubMed]
  • Lopez AF, Williamson DJ, Gamble JR, Begley CG, Harlan JM, Klebanoff SJ, Waltersdorph A, Wong G, Clark SC, Vadas MA. Recombinant human granulocyte-macrophage colony-stimulating factor stimulates in vitro mature human neutrophil and eosinophil function, surface receptor expression, and survival. J Clin Invest. 1986 Nov;78(5):1220–1228. [PMC free article] [PubMed]
  • Ikejima T, Okusawa S, Ghezzi P, van der Meer JW, Dinarello CA. Interleukin-1 induces tumor necrosis factor (TNF) in human peripheral blood mononuclear cells in vitro and a circulating TNF-like activity in rabbits. J Infect Dis. 1990 Jul;162(1):215–223. [PubMed]
  • Van Damme J, Opdenakker G, Simpson RJ, Rubira MR, Cayphas S, Vink A, Billiau A, Van Snick J. Identification of the human 26-kD protein, interferon beta 2 (IFN-beta 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med. 1987 Mar 1;165(3):914–919. [PMC free article] [PubMed]
  • Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest. 1988 Apr;81(4):1162–1172. [PMC free article] [PubMed]
  • Elias JA, Gustilo K, Baeder W, Freundlich B. Synergistic stimulation of fibroblast prostaglandin production by recombinant interleukin 1 and tumor necrosis factor. J Immunol. 1987 Jun 1;138(11):3812–3816. [PubMed]
  • Vogel SN, Kaufman EN, Tate MD, Neta R. Recombinant interleukin-1 alpha and recombinant tumor necrosis factor alpha synergize in vivo to induce early endotoxin tolerance and associated hematopoietic changes. Infect Immun. 1988 Oct;56(10):2650–2657. [PMC free article] [PubMed]
  • Sharon P, Stenson WF. Metabolism of arachidonic acid in acetic acid colitis in rats. Similarity to human inflammatory bowel disease. Gastroenterology. 1985 Jan;88(1 Pt 1):55–63. [PubMed]
  • Wallace JL, MacNaughton WK, Morris GP, Beck PL. Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology. 1989 Jan;96(1):29–36. [PubMed]
  • Eliakim R, Karmeli F, Razin E, Rachmilewitz D. Role of platelet-activating factor in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine and prednisolone. Gastroenterology. 1988 Nov;95(5):1167–1172. [PubMed]
  • Schröder JM. The monocyte-derived neutrophil activating peptide (NAP/interleukin 8) stimulates human neutrophil arachidonate-5-lipoxygenase, but not the release of cellular arachidonate. J Exp Med. 1989 Sep 1;170(3):847–863. [PMC free article] [PubMed]
  • Dinarello CA, Rosenwasser LJ, Wolff SM. Demonstration of a circulating suppressor factor of thymocyte proliferation during endotoxin fever in humans. J Immunol. 1981 Dec;127(6):2517–2519. [PubMed]
  • Liao Z, Grimshaw RS, Rosenstreich DL. Identification of a specific interleukin 1 inhibitor in the urine of febrile patients. J Exp Med. 1984 Jan 1;159(1):126–136. [PMC free article] [PubMed]
  • Seckinger P, Lowenthal JW, Williamson K, Dayer JM, MacDonald HR. A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol. 1987 Sep 1;139(5):1546–1549. [PubMed]
  • Balavoine JF, de Rochemonteix B, Williamson K, Seckinger P, Cruchaud A, Dayer JM. Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). J Clin Invest. 1986 Oct;78(4):1120–1124. [PMC free article] [PubMed]
  • Arend WP, Joslin FG, Thompson RC, Hannum CH. An IL-1 inhibitor from human monocytes. Production and characterization of biologic properties. J Immunol. 1989 Sep 15;143(6):1851–1858. [PubMed]
  • Horuk R, Huang JJ, Covington M, Newton RC. A biochemical and kinetic analysis of the interleukin-1 receptor. Evidence for differences in molecular properties of IL-1 receptors. J Biol Chem. 1987 Dec 5;262(34):16275–16278. [PubMed]
  • Chizzonite R, Truitt T, Kilian PL, Stern AS, Nunes P, Parker KP, Kaffka KL, Chua AO, Lugg DK, Gubler U. Two high-affinity interleukin 1 receptors represent separate gene products. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8029–8033. [PMC free article] [PubMed]
  • Bomsztyk K, Sims JE, Stanton TH, Slack J, McMahan CJ, Valentine MA, Dower SK. Evidence for different interleukin 1 receptors in murine B- and T-cell lines. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8034–8038. [PMC free article] [PubMed]

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