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. 1993 Jul 1;90(13):6155–6159. doi: 10.1073/pnas.90.13.6155

Interleukin 1 signaling occurs exclusively via the type I receptor.

J E Sims 1, M A Gayle 1, J L Slack 1, M R Alderson 1, T A Bird 1, J G Giri 1, F Colotta 1, F Re 1, A Mantovani 1, K Shanebeck 1, et al.
PMCID: PMC46886  PMID: 8327496

Abstract

Two receptors for the proinflammatory cytokine interleukin 1 (IL-1) have been cloned and characterized biochemically. While it has been well established that the type I (80-kDa) IL-1 receptor can mediate responses to IL-1, the function of the type II (60-kDa) IL-1 receptor has been unknown. In this manuscript we describe experiments designed to ask whether the type II receptor is capable of delivering a biological signal. We have examined two types of experimental situation: responses to IL-1 in cells which express predominantly the type II receptor, and responses to IL-1 which have been suggested previously in the literature to be mediated by type II receptors. In both situations we find that the responses instead are mediated via type I receptors. A blocking antibody against the type II receptor never inhibits, and in fact sometimes enhances, the responses. We conclude that a very small number of type I receptors is sufficient to mediate all of the actions of IL-1 which we have examined here and that the function of the type II receptor may not be to transduce signals.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alcamí A., Smith G. L. A soluble receptor for interleukin-1 beta encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection. Cell. 1992 Oct 2;71(1):153–167. doi: 10.1016/0092-8674(92)90274-g. [DOI] [PubMed] [Google Scholar]
  2. Alderson M. R., Tough T. W., Ziegler S. F., Grabstein K. H. Interleukin 7 induces cytokine secretion and tumoricidal activity by human peripheral blood monocytes. J Exp Med. 1991 Apr 1;173(4):923–930. doi: 10.1084/jem.173.4.923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bird T. A., Sleath P. R., deRoos P. C., Dower S. K., Virca G. D. Interleukin-1 represents a new modality for the activation of extracellular signal-regulated kinases/microtubule-associated protein-2 kinases. J Biol Chem. 1991 Nov 25;266(33):22661–22670. [PubMed] [Google Scholar]
  4. Bomsztyk K., Sims J. E., Stanton T. H., Slack J., McMahan C. J., Valentine M. A., Dower S. K. 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. doi: 10.1073/pnas.86.20.8034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bomsztyk K., Stanton T. H., Smith L. L., Rachie N. A., Dower S. K. Properties of interleukin-1 and interferon-gamma receptors in B lymphoid cell line. J Biol Chem. 1989 Apr 15;264(11):6052–6057. [PubMed] [Google Scholar]
  6. Bomsztyk K., Toivola B., Emery D. W., Rooney J. W., Dower S. K., Rachie N. A., Sibley C. H. Role of cAMP in interleukin-1-induced kappa light chain gene expression in murine B cell line. J Biol Chem. 1990 Jun 5;265(16):9413–9417. [PubMed] [Google Scholar]
  7. Carter D. B., Deibel M. R., Jr, Dunn C. J., Tomich C. S., Laborde A. L., Slightom J. L., Berger A. E., Bienkowski M. J., Sun F. F., McEwan R. N. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature. 1990 Apr 12;344(6267):633–638. doi: 10.1038/344633a0. [DOI] [PubMed] [Google Scholar]
  8. Chizzonite R., Truitt T., Kilian P. L., Stern A. S., Nunes P., Parker K. P., Kaffka K. L., Chua A. O., Lugg D. K., 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. doi: 10.1073/pnas.86.20.8029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Colotta F., Peri G., Villa A., Mantovani A. Rapid killing of actinomycin D-treated tumor cells by human mononuclear cells. I. Effectors belong to the monocyte-macrophage lineage. J Immunol. 1984 Feb;132(2):936–944. [PubMed] [Google Scholar]
  10. Curtis B. M., Gallis B., Overell R. W., McMahan C. J., DeRoos P., Ireland R., Eisenman J., Dower S. K., Sims J. E. T-cell interleukin 1 receptor cDNA expressed in Chinese hamster ovary cells regulates functional responses to interleukin 1. Proc Natl Acad Sci U S A. 1989 May;86(9):3045–3049. doi: 10.1073/pnas.86.9.3045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Deyerle K. L., Sims J. E., Dower S. K., Bothwell M. A. Pattern of IL-1 receptor gene expression suggests role in noninflammatory processes. J Immunol. 1992 Sep 1;149(5):1657–1665. [PubMed] [Google Scholar]
  12. Dinarello C. A. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed] [Google Scholar]
  13. Dower S. K., Call S. M., Gillis S., Urdal D. L. Similarity between the interleukin 1 receptors on a murine T-lymphoma cell line and on a murine fibroblast cell line. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1060–1064. doi: 10.1073/pnas.83.4.1060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dower S. K., Kronheim S. R., Hopp T. P., Cantrell M., Deeley M., Gillis S., Henney C. S., Urdal D. L. The cell surface receptors for interleukin-1 alpha and interleukin-1 beta are identical. Nature. 1986 Nov 20;324(6094):266–268. doi: 10.1038/324266a0. [DOI] [PubMed] [Google Scholar]
  15. Dower S. K., Kronheim S. R., March C. J., Conlon P. J., Hopp T. P., Gillis S., Urdal D. L. Detection and characterization of high affinity plasma membrane receptors for human interleukin 1. J Exp Med. 1985 Aug 1;162(2):501–515. doi: 10.1084/jem.162.2.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fanslow W. C., Sims J. E., Sassenfeld H., Morrissey P. J., Gillis S., Dower S. K., Widmer M. B. Regulation of alloreactivity in vivo by a soluble form of the interleukin-1 receptor. Science. 1990 May 11;248(4956):739–742. doi: 10.1126/science.2139736. [DOI] [PubMed] [Google Scholar]
  17. Giri J. G., Kincade P. W., Mizel S. B. Interleukin 1-mediated induction of kappa-light chain synthesis and surface immunoglobulin expression on pre-B cells. J Immunol. 1984 Jan;132(1):223–228. [PubMed] [Google Scholar]
  18. Giri J. G., Newton R. C., Horuk R. Identification of soluble interleukin-1 binding protein in cell-free supernatants. Evidence for soluble interleukin-1 receptor. J Biol Chem. 1990 Oct 15;265(29):17416–17419. [PubMed] [Google Scholar]
  19. Giri J. G., Robb R., Wong W. L., Horuk R. HepG2 cells predominantly express the type II interleukin 1 receptor (biochemical and molecular characterization of the IL-1 receptor). Cytokine. 1992 Jan;4(1):18–23. doi: 10.1016/1043-4666(92)90031-l. [DOI] [PubMed] [Google Scholar]
  20. Granowitz E. V., Clark B. D., Vannier E., Callahan M. V., Dinarello C. A. Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood. 1992 May 1;79(9):2356–2363. [PubMed] [Google Scholar]
  21. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  22. Horuk R., Huang J. J., Covington M., Newton R. C. 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] [Google Scholar]
  23. Horuk R., McCubrey J. A. The interleukin-1 receptor in Raji human B-lymphoma cells. Molecular characterization and evidence for receptor-mediated activation of gene expression. Biochem J. 1989 Jun 15;260(3):657–663. doi: 10.1042/bj2600657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lloyd A. R., Oppenheim J. J. Poly's lament: the neglected role of the polymorphonuclear neutrophil in the afferent limb of the immune response. Immunol Today. 1992 May;13(5):169–172. doi: 10.1016/0167-5699(92)90121-M. [DOI] [PubMed] [Google Scholar]
  25. McMahan C. J., Slack J. L., Mosley B., Cosman D., Lupton S. D., Brunton L. L., Grubin C. E., Wignall J. M., Jenkins N. A., Brannan C. I. A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J. 1991 Oct;10(10):2821–2832. doi: 10.1002/j.1460-2075.1991.tb07831.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Muñoz E., Zubiaga A. M., Sims J. E., Huber B. T. IL-1 signal transduction pathways. I. Two functional IL-1 receptors are expressed in T cells. J Immunol. 1991 Jan 1;146(1):136–143. [PubMed] [Google Scholar]
  27. Orencole S. F., Dinarello C. A. Characterization of a subclone (D10S) of the D10.G4.1 helper T-cell line which proliferates to attomolar concentrations of interleukin-1 in the absence of mitogens. Cytokine. 1989 Nov;1(1):14–22. doi: 10.1016/1043-4666(89)91044-2. [DOI] [PubMed] [Google Scholar]
  28. Ostrowski J., Sims J. E., Sibley C. H., Valentine M. A., Dower S. K., Meier K. E., Bomsztyk K. A serine/threonine kinase activity is closely associated with a 65-kDa phosphoprotein specifically recognized by the kappa B enhancer element. J Biol Chem. 1991 Jul 5;266(19):12722–12733. [PubMed] [Google Scholar]
  29. Rhyne J. A., Mizel S. B., Taylor R. G., Chedid M., McCall C. E. Characterization of the human interleukin 1 receptor on human polymorphonuclear leukocytes. Clin Immunol Immunopathol. 1988 Sep;48(3):354–361. doi: 10.1016/0090-1229(88)90029-3. [DOI] [PubMed] [Google Scholar]
  30. Rogers H. W., Sheehan K. C., Brunt L. M., Dower S. K., Unanue E. R., Schreiber R. D. Interleukin 1 participates in the development of anti-Listeria responses in normal and SCID mice. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1011–1015. doi: 10.1073/pnas.89.3.1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Scapigliati G., Ghiara P., Bartalini M., Tagliabue A., Boraschi D. Differential binding of IL-1 alpha and IL-1 beta to receptors on B and T cells. FEBS Lett. 1989 Jan 30;243(2):394–398. doi: 10.1016/0014-5793(89)80169-3. [DOI] [PubMed] [Google Scholar]
  32. Sims J. E., March C. J., Cosman D., Widmer M. B., MacDonald H. R., McMahan C. J., Grubin C. E., Wignall J. M., Jackson J. L., Call S. M. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science. 1988 Jul 29;241(4865):585–589. doi: 10.1126/science.2969618. [DOI] [PubMed] [Google Scholar]
  33. Sironi M., Breviario F., Proserpio P., Biondi A., Vecchi A., Van Damme J., Dejana E., Mantovani A. IL-1 stimulates IL-6 production in endothelial cells. J Immunol. 1989 Jan 15;142(2):549–553. [PubMed] [Google Scholar]
  34. Slack J., McMahan C. J., Waugh S., Schooley K., Spriggs M. K., Sims J. E., Dower S. K. Independent binding of interleukin-1 alpha and interleukin-1 beta to type I and type II interleukin-1 receptors. J Biol Chem. 1993 Feb 5;268(4):2513–2524. [PubMed] [Google Scholar]
  35. Solari R. Identification and distribution of two forms of the interleukin 1 receptor. Cytokine. 1990 Jan;2(1):21–28. doi: 10.1016/1043-4666(90)90039-v. [DOI] [PubMed] [Google Scholar]
  36. Spriggs M. K., Hruby D. E., Maliszewski C. R., Pickup D. J., Sims J. E., Buller R. M., VanSlyke J. Vaccinia and cowpox viruses encode a novel secreted interleukin-1-binding protein. Cell. 1992 Oct 2;71(1):145–152. doi: 10.1016/0092-8674(92)90273-f. [DOI] [PubMed] [Google Scholar]
  37. Spriggs M. K., Lioubin P. J., Slack J., Dower S. K., Jonas U., Cosman D., Sims J. E., Bauer J. Induction of an interleukin-1 receptor (IL-1R) on monocytic cells. Evidence that the receptor is not encoded by a T cell-type IL-1R mRNA. J Biol Chem. 1990 Dec 25;265(36):22499–22505. [PubMed] [Google Scholar]
  38. Spriggs M. K., Nevens P. J., Grabstein K., Dower S. K., Cosman D., Armitage R. J., McMahan C. J., Sims J. E. Molecular characterization of the interleukin-1 receptor (IL-1R) on monocytes and polymorphonuclear cells. Cytokine. 1992 Mar;4(2):90–95. doi: 10.1016/1043-4666(92)90042-p. [DOI] [PubMed] [Google Scholar]
  39. Stylianou E., O'Neill L. A., Rawlinson L., Edbrooke M. R., Woo P., Saklatvala J. Interleukin 1 induces NF-kappa B through its type I but not its type II receptor in lymphocytes. J Biol Chem. 1992 Aug 5;267(22):15836–15841. [PubMed] [Google Scholar]
  40. Symons J. A., Duff G. W. A soluble form of the interleukin-1 receptor produced by a human B cell line. FEBS Lett. 1990 Oct 15;272(1-2):133–136. doi: 10.1016/0014-5793(90)80466-v. [DOI] [PubMed] [Google Scholar]
  41. Takahashi G. W., Andrews D. F., 3rd, Lilly M. B., Singer J. W., Alderson M. R. Effect of granulocyte-macrophage colony-stimulating factor and interleukin-3 on interleukin-8 production by human neutrophils and monocytes. Blood. 1993 Jan 15;81(2):357–364. [PubMed] [Google Scholar]

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