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Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1997 Nov;4(6):665–670. doi: 10.1128/cdli.4.6.665-670.1997

Interleukin-4 inhibits secretion of interleukin-1beta in the response of human cells to mycobacterial heat shock proteins.

P Méndez-Samperio 1, A Badillo-Flores 1, A Nuñez-Vazquez 1, M Hernandez Garay 1
PMCID: PMC170637  PMID: 9384286

Abstract

Cellular activation induced by Mycobacterium bovis bacillus Calmette-Guérin (BCG) and heat shock proteins (HSP) leads to the production of proinflammatory cytokines such as interleukin-1beta (IL-1beta) and IL-6. In this study, we found that IL-4 significantly suppressed IL-1beta secretion induced by BCG and the 70- and 65-kDa HSP. When exogenous recombinant human IL-4 was added to human mononuclear cells, a dose- and time-related inhibition of the 70-kDa HSP- and BCG-induced IL-1beta secretion was observed. IL-1beta secretion was maximally inhibited at 24 h of culture, and this inhibitory effect was sustained at a later time point of culture (120 h). In addition, IL-2, another T-cell-derived cytokine acting on monocytes, had no effect on IL-1beta secretion induced by either BCG or the 70-kDa HSP, indicating that in these experiments not all cytokines could immunoregulate IL-1beta secretion. This inhibitory effect was not due to a cytotoxic effect of IL-4, since the viabilities of human mononuclear cells were comparable in the presence and absence of IL-4. IL-4 was also able to inhibit the secretion of IL-1beta by mycobacterium-stimulated cells from three rheumatoid arthritis patients. This inhibitory effect of IL-4 was reversed with a blocking anti-IL-4 antibody. Finally, IL-4 inhibited IL-6 secretion by mycobacterium-activated human cells. These results suggest that IL-4 may be important in the regulation of the immune response to mycobacterial antigens.

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Selected References

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  1. Arend W. P., Dayer J. M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990 Mar;33(3):305–315. doi: 10.1002/art.1780330302. [DOI] [PubMed] [Google Scholar]
  2. Arend W. P. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest. 1991 Nov;88(5):1445–1451. doi: 10.1172/JCI115453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bevilacqua M. P., Pober J. S., Wheeler M. E., Cotran R. S., Gimbrone M. A., Jr Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest. 1985 Nov;76(5):2003–2011. doi: 10.1172/JCI112200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brennan F. M., Chantry D., Jackson A., Maini R., Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989 Jul 29;2(8657):244–247. doi: 10.1016/s0140-6736(89)90430-3. [DOI] [PubMed] [Google Scholar]
  5. Cope A. P., Gibbons D. L., Aderka D., Foxwell B. M., Wallach D., Maini R. N., Feldmann M., Brennan F. M. Differential regulation of tumour necrosis factor receptors (TNF-R) by IL-4; upregulation of P55 and P75 TNF-R on synovial joint mononuclear cells. Cytokine. 1993 May;5(3):205–212. doi: 10.1016/1043-4666(93)90006-q. [DOI] [PubMed] [Google Scholar]
  6. Dayer J. M., de Rochemonteix B., Burrus B., Demczuk S., Dinarello C. A. Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells. J Clin Invest. 1986 Feb;77(2):645–648. doi: 10.1172/JCI112350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Donnelly R. P., Fenton M. J., Finbloom D. S., Gerrard T. L. Differential regulation of IL-1 production in human monocytes by IFN-gamma and IL-4. J Immunol. 1990 Jul 15;145(2):569–575. [PubMed] [Google Scholar]
  8. Donnelly R. P., Fenton M. J., Kaufman J. D., Gerrard T. L. IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4. J Immunol. 1991 May 15;146(10):3431–3436. [PubMed] [Google Scholar]
  9. Eisenberg S. P., Evans R. J., Arend W. P., Verderber E., Brewer M. T., Hannum C. H., Thompson R. C. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. doi: 10.1038/343341a0. [DOI] [PubMed] [Google Scholar]
  10. Essner R., Rhoades K., McBride W. H., Morton D. L., Economou J. S. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol. 1989 Jun 1;142(11):3857–3861. [PubMed] [Google Scholar]
  11. Firestein G. S., Alvaro-Gracia J. M., Maki R., Alvaro-Garcia J. M. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol. 1990 May 1;144(9):3347–3353. [PubMed] [Google Scholar]
  12. Flesch I. E., Kaufmann S. H. Activation of tuberculostatic macrophage functions by gamma interferon, interleukin-4, and tumor necrosis factor. Infect Immun. 1990 Aug;58(8):2675–2677. doi: 10.1128/iai.58.8.2675-2677.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Friedland J. S., Shattock R., Remick D. G., Griffin G. E. Mycobacterial 65-kD heat shock protein induces release of proinflammatory cytokines from human monocytic cells. Clin Exp Immunol. 1993 Jan;91(1):58–62. doi: 10.1111/j.1365-2249.1993.tb03354.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hart P. H., Ahern M. J., Smith M. D., Finlay-Jones J. J. Comparison of the suppressive effects of interleukin-10 and interleukin-4 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis. Immunology. 1995 Apr;84(4):536–542. [PMC free article] [PubMed] [Google Scholar]
  15. Kandel R. A., Petelycky M., Dinarello C. A., Minden M., Pritzker K. P., Cruz T. F. Comparison of the effect of interleukin 6 and interleukin 1 on collagenase and proteoglycan production by chondrocytes. J Rheumatol. 1990 Jul;17(7):953–957. [PubMed] [Google Scholar]
  16. Lamb J. R., Bal V., Mendez-Samperio P., Mehlert A., So A., Rothbard J., Jindal S., Young R. A., Young D. B. Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1(2):191–196. doi: 10.1093/intimm/1.2.191. [DOI] [PubMed] [Google Scholar]
  17. Launois P., Vandenbussche P., M'Bayame N. N., Drowart A., Van Vooren J. P., Sarthou J. L., Millan J., Huygen K. IL-6 production in response to purified mycobacterial heat-shock proteins and to antigen 85 in leprosy. Cell Immunol. 1993 May;148(2):283–290. doi: 10.1006/cimm.1993.1112. [DOI] [PubMed] [Google Scholar]
  18. Lewis C., Mazzei G., Shaw A. Monoclonal antibodies reacting with the interleukin 1 receptor define a multi-molecular complex. Eur J Immunol. 1990 Jan;20(1):207–213. doi: 10.1002/eji.1830200130. [DOI] [PubMed] [Google Scholar]
  19. Martin J., Horwich A. L., Hartl F. U. Prevention of protein denaturation under heat stress by the chaperonin Hsp60. Science. 1992 Nov 6;258(5084):995–998. doi: 10.1126/science.1359644. [DOI] [PubMed] [Google Scholar]
  20. McIntyre K. W., Stepan G. J., Kolinsky K. D., Benjamin W. R., Plocinski J. M., Kaffka K. L., Campen C. A., Chizzonite R. A., Kilian P. L. 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. doi: 10.1084/jem.173.4.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miossec P. The role of interleukin 1 in the pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 1987 Oct-Dec;5(4):305–308. [PubMed] [Google Scholar]
  22. Morrison D. C., Jacobs D. M. Binding of polymyxin B to the lipid A portion of bacterial lipopolysaccharides. Immunochemistry. 1976 Oct;13(10):813–818. doi: 10.1016/0019-2791(76)90181-6. [DOI] [PubMed] [Google Scholar]
  23. Mutis T., Kraakman E. M., Cornelisse Y. E., Haanen J. B., Spits H., De Vries R. R., Ottenhoff T. H. Analysis of cytokine production by Mycobacterium-reactive T cells. Failure to explain Mycobacterium leprae-specific nonresponsiveness of peripheral blood T cells from lepromatous leprosy patients. J Immunol. 1993 May 15;150(10):4641–4651. [PubMed] [Google Scholar]
  24. Peetermans W. E., Raats C. J., Langermans J. A., van Furth R. Mycobacterial heat-shock protein 65 induces proinflammatory cytokines but does not activate human mononuclear phagocytes. Scand J Immunol. 1994 Jun;39(6):613–617. doi: 10.1111/j.1365-3083.1994.tb03421.x. [DOI] [PubMed] [Google Scholar]
  25. Powrie F., Menon S., Coffman R. L. Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol. 1993 Nov;23(11):3043–3049. doi: 10.1002/eji.1830231147. [DOI] [PubMed] [Google Scholar]
  26. Quayle A. J., Wilson K. B., Li S. G., Kjeldsen-Kragh J., Oftung F., Shinnick T., Sioud M., Førre O., Capra J. D., Natvig J. B. Peptide recognition, T cell receptor usage and HLA restriction elements of human heat-shock protein (hsp) 60 and mycobacterial 65-kDa hsp-reactive T cell clones from rheumatoid synovial fluid. Eur J Immunol. 1992 May;22(5):1315–1322. doi: 10.1002/eji.1830220529. [DOI] [PubMed] [Google Scholar]
  27. Rossi V., Breviario F., Ghezzi P., Dejana E., Mantovani A. Prostacyclin synthesis induced in vascular cells by interleukin-1. Science. 1985 Jul 12;229(4709):174–176. doi: 10.1126/science.2409598. [DOI] [PubMed] [Google Scholar]
  28. Seckinger P., Klein-Nulend J., Alander C., Thompson R. C., Dayer J. M., Raisz L. G. 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] [Google Scholar]
  29. Tsoulfa G., Rook G. A., Van-Embden J. D., Young D. B., Mehlert A., Isenberg D. A., Hay F. C., Lydyard P. M. Raised serum IgG and IgA antibodies to mycobacterial antigens in rheumatoid arthritis. Ann Rheum Dis. 1989 Feb;48(2):118–123. doi: 10.1136/ard.48.2.118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vannier E., Miller L. C., Dinarello C. A. Coordinated antiinflammatory effects of interleukin 4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4076–4080. doi: 10.1073/pnas.89.9.4076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wallis R. S., Amir-Tahmasseb M., Ellner J. J. Induction of interleukin 1 and tumor necrosis factor by mycobacterial proteins: the monocyte western blot. Proc Natl Acad Sci U S A. 1990 May;87(9):3348–3352. doi: 10.1073/pnas.87.9.3348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Watanabe K., Tanaka Y., Morimoto I., Yahata K., Zeki K., Fujihira T., Yamashita U., Eto S. Interleukin-4 as a potent inhibitor of bone resorption. Biochem Biophys Res Commun. 1990 Nov 15;172(3):1035–1041. doi: 10.1016/0006-291x(90)91550-c. [DOI] [PubMed] [Google Scholar]
  33. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. van Eden W. Heat-shock proteins as immunogenic bacterial antigens with the potential to induce and regulate autoimmune arthritis. Immunol Rev. 1991 Jun;121:5–28. doi: 10.1111/j.1600-065x.1991.tb00821.x. [DOI] [PubMed] [Google Scholar]

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