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. 1993 Feb 1;177(2):551–555. doi: 10.1084/jem.177.2.551

In vivo induction of interleukin 10 by anti-CD3 monoclonal antibody or bacterial lipopolysaccharide: differential modulation by cyclosporin A

PMCID: PMC2190912  PMID: 8426125

Abstract

We investigated the in vivo effects of cyclosporin A (CsA) on the production of interleukin (IL) 10, a cytokine with major immunosuppressive properties. To elicit IL-10 production in vivo, BALB/c mice were injected either with the anti-mouse CD3 145-2C11 monoclonal antibody (mAb) (25 micrograms) or with bacterial lipopolysaccharide (LPS) (20 micrograms). A systemic release of IL-10 was observed in both models, IL-10 serum levels reaching 1.60 +/- 0.32 U/ml (mean +/- SEM) and 0.67 +/- 0.09 U/ml 6 h after injection of 145- 2C11 mAb and LPS, respectively. Experiments in nude mice indicated that T cells are involved in the induction of IL-10 by anti-CD3 mAb, but not by LPS. Pretreatment with CsA (total dose: 50 mg/kg) before injection of 145-2C11 mAb completely prevented the release of IL-10 in serum as well as IL-10 mRNA accumulation in spleen cells. In contrast, CsA markedly enhanced LPS-induced IL-10 release (IL-10 serum levels at 6 h: 8.31 +/- 0.43 vs. 0.71 +/- 0.15 U/ml in mice pretreated with CsA vehicle-control, p < 0.001), as well as IL-10 mRNA accumulation in spleen. We conclude that CsA differentially affects IL-10 production in vivo depending on the nature of the eliciting agent. This observation might be relevant to clinical settings, especially in organ transplantation.

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Selected References

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  1. Abramowicz D., Goldman M., De Pauw L., Vanherweghem J. L., Kinnaert P., Vereerstraeten P. The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation--a single-center, prospective, randomized study. Transplantation. 1992 Sep;54(3):433–437. doi: 10.1097/00007890-199209000-00009. [DOI] [PubMed] [Google Scholar]
  2. Alegre M. L., Vandenabeele P., Depierreux M., Florquin S., Deschodt-Lanckman M., Flamand V., Moser M., Leo O., Urbain J., Fiers W. Cytokine release syndrome induced by the 145-2C11 anti-CD3 monoclonal antibody in mice: prevention by high doses of methylprednisolone. J Immunol. 1991 Feb 15;146(4):1184–1191. [PubMed] [Google Scholar]
  3. Alegre M., Vandenabeele P., Flamand V., Moser M., Leo O., Abramowicz D., Urbain J., Fiers W., Goldman M. Hypothermia and hypoglycemia induced by anti-CD3 monoclonal antibody in mice: role of tumor necrosis factor. Eur J Immunol. 1990 Mar;20(3):707–710. doi: 10.1002/eji.1830200337. [DOI] [PubMed] [Google Scholar]
  4. Altmeyer A., Staruch M. J., Fischer P. A., Durette P. L., Tocci M. J., Sigal N. H., Dumont F. J. Unexpected up-regulation of gene expression by cyclosporin A and FK-506 in a T-cell lymphoma: both immunosuppressants augment Ly-6E antigen induction by interferon-gamma in the presence of ionomycin. Int J Immunopharmacol. 1991;13(8):1187–1199. doi: 10.1016/0192-0561(91)90170-c. [DOI] [PubMed] [Google Scholar]
  5. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fiorentino D. F., Zlotnik A., Mosmann T. R., Howard M., O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed] [Google Scholar]
  7. Fiorentino D. F., Zlotnik A., Vieira P., Mosmann T. R., Howard M., Moore K. W., O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991 May 15;146(10):3444–3451. [PubMed] [Google Scholar]
  8. Flamand V., Abramowicz D., Goldman M., Biernaux C., Huez G., Urbain J., Moser M., Leo O. Anti-CD3 antibodies induce T cells from unprimed animals to secrete IL-4 both in vitro and in vivo. J Immunol. 1990 Apr 15;144(8):2875–2882. [PubMed] [Google Scholar]
  9. Fong Y., Tracey K. J., Moldawer L. L., Hesse D. G., Manogue K. B., Kenney J. S., Lee A. T., Kuo G. C., Allison A. C., Lowry S. F. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J Exp Med. 1989 Nov 1;170(5):1627–1633. doi: 10.1084/jem.170.5.1627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Granelli-Piperno A. Lymphokine gene expression in vivo is inhibited by cyclosporin A. J Exp Med. 1990 Feb 1;171(2):533–544. doi: 10.1084/jem.171.2.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grbic J. T., Mannick J. A., Gough D. B., Rodrick M. L. The role of prostaglandin E2 in immune suppression following injury. Ann Surg. 1991 Sep;214(3):253–263. doi: 10.1097/00000658-199109000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hirsch R., Eckhaus M., Auchincloss H., Jr, Sachs D. H., Bluestone J. A. Effects of in vivo administration of anti-T3 monoclonal antibody on T cell function in mice. I. Immunosuppression of transplantation responses. J Immunol. 1988 Jun 1;140(11):3766–3772. [PubMed] [Google Scholar]
  13. Howard M., O'Garra A. Biological properties of interleukin 10. Immunol Today. 1992 Jun;13(6):198–200. doi: 10.1016/0167-5699(92)90153-X. [DOI] [PubMed] [Google Scholar]
  14. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Li B., Sehajpal P. K., Khanna A., Vlassara H., Cerami A., Stenzel K. H., Suthanthiran M. Differential regulation of transforming growth factor beta and interleukin 2 genes in human T cells: demonstration by usage of novel competitor DNA constructs in the quantitative polymerase chain reaction. J Exp Med. 1991 Nov 1;174(5):1259–1262. doi: 10.1084/jem.174.5.1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Moore K. W., Vieira P., Fiorentino D. F., Trounstine M. L., Khan T. A., Mosmann T. R. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science. 1990 Jun 8;248(4960):1230–1234. doi: 10.1126/science.2161559. [DOI] [PubMed] [Google Scholar]
  17. Mosmann T. R., Schumacher J. H., Fiorentino D. F., Leverah J., Moore K. W., Bond M. W. Isolation of monoclonal antibodies specific for IL-4, IL-5, IL-6, and a new Th2-specific cytokine (IL-10), cytokine synthesis inhibitory factor, by using a solid phase radioimmunoadsorbent assay. J Immunol. 1990 Nov 1;145(9):2938–2945. [PubMed] [Google Scholar]
  18. Murray L. J., Lee R., Martens C. In vivo cytokine gene expression in T cell subsets of the autoimmune MRL/Mp-lpr/lpr mouse. Eur J Immunol. 1990 Jan;20(1):163–170. doi: 10.1002/eji.1830200124. [DOI] [PubMed] [Google Scholar]
  19. O'Garra A., Chang R., Go N., Hastings R., Haughton G., Howard M. Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur J Immunol. 1992 Mar;22(3):711–717. doi: 10.1002/eji.1830220314. [DOI] [PubMed] [Google Scholar]
  20. O'Garra A., Stapleton G., Dhar V., Pearce M., Schumacher J., Rugo H., Barbis D., Stall A., Cupp J., Moore K. Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. Int Immunol. 1990;2(9):821–832. doi: 10.1093/intimm/2.9.821. [DOI] [PubMed] [Google Scholar]
  21. Persson U. Lipopolysaccharide-induced suppression of the primary immune response to a thymus-dependent antigen. J Immunol. 1977 Mar;118(3):789–796. [PubMed] [Google Scholar]
  22. Scott D. E., Gause W. C., Finkelman F. D., Steinberg A. D. Anti-CD3 antibody induces rapid expression of cytokine genes in vivo. J Immunol. 1990 Oct 1;145(7):2183–2188. [PubMed] [Google Scholar]
  23. Sigal N. H., Dumont F. J. Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992;10:519–560. doi: 10.1146/annurev.iy.10.040192.002511. [DOI] [PubMed] [Google Scholar]
  24. Svetić A., Finkelman F. D., Jian Y. C., Dieffenbach C. W., Scott D. E., McCarthy K. F., Steinberg A. D., Gause W. C. Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody. J Immunol. 1991 Oct 1;147(7):2391–2397. [PubMed] [Google Scholar]
  25. Walz G., Zanker B., Melton L. B., Suthanthiran M., Strom T. B. Possible association of the immunosuppressive and B cell lymphoma-promoting properties of cyclosporine. Transplantation. 1990 Jan;49(1):191–194. doi: 10.1097/00007890-199001000-00042. [DOI] [PubMed] [Google Scholar]
  26. Wang S. C., Zeevi A., Jordan M. L., Simmons R. L., Tweardy D. J. FK 506, rapamycin, and cyclosporine: effects on IL-4 and IL-10 mRNA levels in a T-helper 2 cell line. Transplant Proc. 1991 Dec;23(6):2920–2922. [PubMed] [Google Scholar]

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