Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Nov 1991; 88(5): 1445–1451.
PMCID: PMC295645

Interleukin 1 receptor antagonist. A new member of the interleukin 1 family.

Abstract

This review has summarized recent information derived from many laboratories on the discovery, characteristics, and properties of a new member of the IL-1 family, IL-1 receptor antagonist. In addition to information, an emphasis has been placed on unanswered questions and new concepts. The existence of this first-described naturally occurring specific cytokine receptor antagonist may lead to a different perspective on the cytokine network. A major unanswered question emphasized throughout this review, that now can be addressed more directly, concerns what are the physiological roles of members of the IL-1 family. Although IL-1 beta is presumed to function primarily as an extracellular cytokine, this molecule lacks a leader peptide, is synthesized and handled by the cells in a manner suggestive of a cytoplasmic (not secretory) protein, and may only be released after cellular injury. Furthermore, although IL-1ra possesses a leader sequence, 50% or more of this protein remains cell associated. Do these observations suggest that members of the IL-1 family possess important intracellular functions, as yet undetermined? IL-1 alpha may play an intracellular role in regulating senescence; an IL-1 alpha antisense oligodeoxynucleotide was shown to prolong the life span of cultured human endothelial cells. Whether intracellular IL-1ra plays a role in influencing life span has not been determined. The discovery of IL-1ra has led to a first level of assumptions that this molecule may be functioning in vivo to regulate the pleiotropic extracellular effects of IL-1 in physiological or pathophysiological processes. Although enticing, these assumptions have not yet been proven to be true. Perhaps we need to look beyond, or within, and consider that IL-1ra and other members of the IL-1 family may have additional roles in normal or abnormal cell growth and development.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed]
  • Larrick JW. Native interleukin 1 inhibitors. Immunol Today. 1989 Feb;10(2):61–66. [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]
  • Arend WP, Joslin FG, Massoni RJ. Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor. J Immunol. 1985 Jun;134(6):3868–3875. [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]
  • 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]
  • Seckinger P, Williamson K, Balavoine JF, Mach B, Mazzei G, Shaw A, Dayer JM. A urine inhibitor of interleukin 1 activity affects both interleukin 1 alpha and 1 beta but not tumor necrosis factor alpha. J Immunol. 1987 Sep 1;139(5):1541–1545. [PubMed]
  • Seckinger P, Yaron I, Meyer FA, Yaron M, Dayer JM. Modulation of the effects of interleukin-1 on glycosaminoglycan synthesis by the urine-derived interleukin-1 inhibitor, but not by interleukin-6. Arthritis Rheum. 1990 Dec;33(12):1807–1814. [PubMed]
  • Seckinger P, Klein-Nulend J, Alander C, Thompson RC, Dayer JM, Raisz LG. Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production. J Immunol. 1990 Dec 15;145(12):4181–4184. [PubMed]
  • Dayer-Métroz MD, Wollheim CB, Seckinger P, Dayer JM. A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets. J Autoimmun. 1989 Apr;2(2):163–171. [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]
  • 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]
  • Eisenberg SP, Brewer MT, Verderber E, Heimdal P, Brandhuber BJ, Thompson RC. Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5232–5236. [PMC free article] [PubMed]
  • Zahedi K, Seldin MF, Rits M, Ezekowitz RA, Whitehead AS. Mouse IL-1 receptor antagonist protein. Molecular characterization, gene mapping, and expression of mRNA in vitro and in vivo. J Immunol. 1991 Jun 15;146(12):4228–4233. [PubMed]
  • Carter DB, Deibel MR, Jr, Dunn CJ, Tomich CS, Laborde AL, Slightom JL, Berger AE, Bienkowski MJ, Sun FF, McEwan RN, et al. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature. 1990 Apr 12;344(6267):633–638. [PubMed]
  • Bienkowski MJ, Eessalu TE, Berger AE, Truesdell SE, Shelly JA, Laborde AL, Zurcher-Neely HA, Reardon IM, Heinrikson RL, Chosay JG, et al. Purification and characterization of interleukin 1 receptor level antagonist proteins from THP-1 cells. J Biol Chem. 1990 Aug 25;265(24):14505–14511. [PubMed]
  • Mazzei GJ, Bernasconi LM, Lewis C, Mermod JJ, Kindler V, Shaw AR. Human granulocyte-macrophage colony-stimulating factor plus phorbol myristate acetate stimulate a promyelocytic cell line to produce an IL-1 inhibitor. J Immunol. 1990 Jul 15;145(2):585–591. [PubMed]
  • Mazzei GJ, Seckinger PL, Dayer JM, Shaw AR. Purification and characterization of a 26-kDa competitive inhibitor of interleukin 1. Eur J Immunol. 1990 Mar;20(3):683–689. [PubMed]
  • Haskill S, Martin G, Van Le L, Morris J, Peace A, Bigler CF, Jaffe GJ, Hammerberg C, Sporn SA, Fong S, et al. cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3681–3685. [PMC free article] [PubMed]
  • Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem. 1991 Jun 5;266(16):10331–10336. [PubMed]
  • Gehrke L, Jobling SA, Paik LS, McDonald B, Rosenwasser LJ, Auron PE. A point mutation uncouples human interleukin-1 beta biological activity and receptor binding. J Biol Chem. 1990 Apr 15;265(11):5922–5925. [PubMed]
  • Yamayoshi M, Ohue M, Kawashima H, Kotani H, IIda M, Kawata S, Yamada M. A human IL-1 alpha derivative which lacks prostaglandin E2 inducing activity and inhibits the activity of IL-1 through receptor competition. Lymphokine Res. 1990 Fall;9(3):405–413. [PubMed]
  • Ju G, Labriola-Tompkins E, Campen CA, Benjamin WR, Karas J, Plocinski J, Biondi D, Kaffka KL, Kilian PL, Eisenberg SP, et al. Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2658–2662. [PMC free article] [PubMed]
  • Granowitz EV, Clark BD, Mancilla J, Dinarello CA. Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem. 1991 Aug 5;266(22):14147–14150. [PubMed]
  • McIntyre KW, Stepan GJ, Kolinsky KD, Benjamin WR, Plocinski JM, Kaffka KL, Campen CA, Chizzonite RA, Kilian PL. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med. 1991 Apr 1;173(4):931–939. [PMC free article] [PubMed]
  • Malyak M, Joslin FG, Verderber EL, Eisenberg SP, Arend WP. IL-1ra ELISA: reduction and alkylation of synovial fluid eliminates interference by IgM rheumatoid factors. J Immunol Methods. 1991 Jul 5;140(2):281–288. [PubMed]
  • Arend WP, Smith MF, Jr, Janson RW, Joslin FG. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol. 1991 Sep 1;147(5):1530–1536. [PubMed]
  • Schur PH, Chang DM, Baptiste P, Uhteg LC, Hanson DC. Human monocytes produce IL-1 and an inhibitor of IL-1 in response to two different signals. Clin Immunol Immunopathol. 1990 Oct;57(1):45–63. [PubMed]
  • Poutsiaka DD, Clark BD, Vannier E, Dinarello CA. Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated. Blood. 1991 Sep 1;78(5):1275–1281. [PubMed]
  • Roux-Lombard P, Modoux C, Dayer JM. Production of interleukin-1 (IL-1) and a specific IL-1 inhibitor during human monocyte-macrophage differentiation: influence of GM-CSF. Cytokine. 1989 Nov;1(1):45–51. [PubMed]
  • Shields J, Bernasconi LM, Benotto W, Shaw AR, Mazzei GJ. Production of a 26,000-dalton interleukin 1 inhibitor by human monocytes is regulated by granulocyte-macrophage colony-stimulating factor. Cytokine. 1990 Mar;2(2):122–128. [PubMed]
  • Turner M, Chantry D, Katsikis P, Berger A, Brennan FM, Feldmann M. Induction of the interleukin 1 receptor antagonist protein by transforming growth factor-beta. Eur J Immunol. 1991 Jul;21(7):1635–1639. [PubMed]
  • Galve-de Rochemonteix B, Nicod LP, Junod AF, Dayer JM. Characterization of a specific 20- to 25-kD interleukin-1 inhibitor from cultured human lung macrophages. Am J Respir Cell Mol Biol. 1990 Oct;3(4):355–361. [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]
  • Chang TL, Shea CM, Urioste S, Thompson RC, Boom WH, Abbas AK. Heterogeneity of helper/inducer T lymphocytes. III. Responses of IL-2- and IL-4-producing (Th1 and Th2) clones to antigens presented by different accessory cells. J Immunol. 1990 Nov 1;145(9):2803–2808. [PubMed]
  • Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990 Mar;33(3):305–315. [PubMed]
  • Smith RJ, Chin JE, Sam LM, Justen JM. Biologic effects of an interleukin-1 receptor antagonist protein on interleukin-1-stimulated cartilage erosion and chondrocyte responsiveness. Arthritis Rheum. 1991 Jan;34(1):78–83. [PubMed]
  • Henderson B, Thompson RC, Hardingham T, Lewthwaite J. Inhibition of interleukin-1-induced synovitis and articular cartilage proteoglycan loss in the rabbit knee by recombinant human interleukin-1 receptor antagonist. Cytokine. 1991 May;3(3):246–249. [PubMed]
  • Olds LC, Miller JJ., 3rd C3 activation products correlate with antibodies to lipid A in pauciarticular juvenile arthritis. Arthritis Rheum. 1990 Apr;33(4):520–524. [PubMed]
  • Prieur AM, Kaufmann MT, Griscelli C, Dayer JM. Specific interleukin-1 inhibitor in serum and urine of children with systemic juvenile chronic arthritis. Lancet. 1987 Nov 28;2(8570):1240–1242. [PubMed]
  • Ulich TR, Yin SM, Guo KZ, del Castillo J, Eisenberg SP, Thompson RC. The intratracheal administration of endotoxin and cytokines. III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin- and IL-1-induced acute inflammation. Am J Pathol. 1991 Mar;138(3):521–524. [PMC free article] [PubMed]
  • Henricson BE, Neta R, Vogel SN. An interleukin-1 receptor antagonist blocks lipopolysaccharide-induced colony-stimulating factor production and early endotoxin tolerance. Infect Immun. 1991 Mar;59(3):1188–1191. [PMC free article] [PubMed]
  • Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson RC. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature. 1990 Dec 6;348(6301):550–552. [PubMed]
  • Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA. A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. FASEB J. 1991 Mar 1;5(3):338–343. [PubMed]
  • Alexander HR, Doherty GM, Buresh CM, Venzon DJ, Norton JA. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med. 1991 Apr 1;173(4):1029–1032. [PMC free article] [PubMed]
  • Spinas GA, Bloesch D, Kaufmann MT, Keller U, Dayer JM. Induction of plasma inhibitors of interleukin 1 and TNF-alpha activity by endotoxin administration to normal humans. Am J Physiol. 1990 Nov;259(5 Pt 2):R993–R997. [PubMed]
  • Cominelli F, Nast CC, Clark BD, Schindler R, Lierena R, Eysselein VE, Thompson RC, Dinarello CA. Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J Clin Invest. 1990 Sep;86(3):972–980. [PMC free article] [PubMed]
  • Opp MR, Krueger JM. Interleukin 1-receptor antagonist blocks interleukin 1-induced sleep and fever. Am J Physiol. 1991 Feb;260(2 Pt 2):R453–R457. [PubMed]
  • Maier JA, Voulalas P, Roeder D, Maciag T. Extension of the life-span of human endothelial cells by an interleukin-1 alpha antisense oligomer. Science. 1990 Sep 28;249(4976):1570–1574. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • OMIM
    OMIM
    OMIM record citing PubMed
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...