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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Jul;90(1):262–266. doi: 10.1172/JCI115846

Recombinant interleukin-12 suppresses the synthesis of immunoglobulin E by interleukin-4 stimulated human lymphocytes.

M Kiniwa 1, M Gately 1, U Gubler 1, R Chizzonite 1, C Fargeas 1, G Delespesse 1
PMCID: PMC443090  PMID: 1353081

Abstract

Interleukin-12 is a recently discovered lymphokine displaying an array of in vitro activities suggesting a major role in protective immunity against infectious agents like viruses. This study provides evidence that IL-12 may also be implicated in the selection of the immunoglobulin isotypes. We show that picomolar concentrations of rIL-12 markedly inhibit the synthesis of IgE by IL-4-stimulated PBMC. The suppression of IgE is observed at the protein and at the mRNA levels, it is isotype specific, and it is abolished by neutralizing anti-IL-12 mAbs. IL-12 may suppress IgE synthesis by: (a) inducing the production of IFN-gamma, a known inhibitor of IgE synthesis and (b) by a novel mechanism which is IFN-gamma independent. The best evidence for this is from studies on IgE synthesis by IL-4-plus hydrocortisone-stimulated umbilical cord blood lymphocytes, which do not produce detectable amounts of IFN-gamma. In such cultures, rIL-12 inhibits IgE synthesis even in the presence of a large excess of neutralizing anti-IFN-gamma mAb.

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Selected References

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  1. Chan S. H., Perussia B., Gupta J. W., Kobayashi M., Pospísil M., Young H. A., Wolf S. F., Young D., Clark S. C., Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. doi: 10.1084/jem.173.4.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chizzonite R., Truitt T., Podlaski F. J., Wolitzky A. G., Quinn P. M., Nunes P., Stern A. S., Gately M. K. IL-12: monoclonal antibodies specific for the 40-kDa subunit block receptor binding and biologic activity on activated human lymphoblasts. J Immunol. 1991 Sep 1;147(5):1548–1556. [PubMed] [Google Scholar]
  3. Coffman R. L., Varkila K., Scott P., Chatelain R. Role of cytokines in the differentiation of CD4+ T-cell subsets in vivo. Immunol Rev. 1991 Oct;123:189–207. doi: 10.1111/j.1600-065x.1991.tb00611.x. [DOI] [PubMed] [Google Scholar]
  4. Fernandez-Botran R., Sanders V. M., Mosmann T. R., Vitetta E. S. Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells. J Exp Med. 1988 Aug 1;168(2):543–558. doi: 10.1084/jem.168.2.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Finkelman F. D., Holmes J., Katona I. M., Urban J. F., Jr, Beckmann M. P., Park L. S., Schooley K. A., Coffman R. L., Mosmann T. R., Paul W. E. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. doi: 10.1146/annurev.iy.08.040190.001511. [DOI] [PubMed] [Google Scholar]
  6. Finkelman F. D., Svetic A., Gresser I., Snapper C., Holmes J., Trotta P. P., Katona I. M., Gause W. C. Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice. J Exp Med. 1991 Nov 1;174(5):1179–1188. doi: 10.1084/jem.174.5.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gajewski T. F., Fitch F. W. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245–4252. [PubMed] [Google Scholar]
  8. Gascan H., Gauchat J. F., Roncarolo M. G., Yssel H., Spits H., de Vries J. E. Human B cell clones can be induced to proliferate and to switch to IgE and IgG4 synthesis by interleukin 4 and a signal provided by activated CD4+ T cell clones. J Exp Med. 1991 Mar 1;173(3):747–750. doi: 10.1084/jem.173.3.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gately M. K., Desai B. B., Wolitzky A. G., Quinn P. M., Dwyer C. M., Podlaski F. J., Familletti P. C., Sinigaglia F., Chizonnite R., Gubler U. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol. 1991 Aug 1;147(3):874–882. [PubMed] [Google Scholar]
  10. Gauchat J. F., Lebman D. A., Coffman R. L., Gascan H., de Vries J. E. Structure and expression of germline epsilon transcripts in human B cells induced by interleukin 4 to switch to IgE production. J Exp Med. 1990 Aug 1;172(2):463–473. doi: 10.1084/jem.172.2.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gubler U., Chua A. O., Schoenhaut D. S., Dwyer C. M., McComas W., Motyka R., Nabavi N., Wolitzky A. G., Quinn P. M., Familletti P. C. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. doi: 10.1073/pnas.88.10.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jabara H. H., Schneider L. C., Shapira S. K., Alfieri C., Moody C. T., Kieff E., Geha R. S., Vercelli D. Induction of germ-line and mature C epsilon transcripts in human B cells stimulated with rIL-4 and EBV. J Immunol. 1990 Nov 15;145(10):3468–3473. [PubMed] [Google Scholar]
  13. Kibler R., Hicks M. J., Wright A. L., Taussig L. M. A comparative analysis of cord blood and adult lymphocytes: interleukin-2 and interferon production, natural killer cell activity, and lymphocyte populations. Diagn Immunol. 1986;4(4):201–208. [PubMed] [Google Scholar]
  14. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Peleman R., Delespesse G. In vitro synthesis of human IgE by neonatal lymphocytes: enhancing effect of interferon-gamma. Cell Immunol. 1990 Sep;129(2):299–309. doi: 10.1016/0008-8749(90)90206-7. [DOI] [PubMed] [Google Scholar]
  16. Peleman R., Wu J., Fargeas C., Delespesse G. Recombinant interleukin 4 suppresses the production of interferon gamma by human mononuclear cells. J Exp Med. 1989 Nov 1;170(5):1751–1756. doi: 10.1084/jem.170.5.1751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pène J., Rousset F., Brière F., Chrétien I., Bonnefoy J. Y., Spits H., Yokota T., Arai N., Arai K., Banchereau J. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6880–6884. doi: 10.1073/pnas.85.18.6880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rousset F., Garcia E., Banchereau J. Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J Exp Med. 1991 Mar 1;173(3):705–710. doi: 10.1084/jem.173.3.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sarfati M., Delespesse G. Possible role of human lymphocyte receptor for IgE (CD23) or its soluble fragments in the in vitro synthesis of human IgE. J Immunol. 1988 Oct 1;141(7):2195–2199. [PubMed] [Google Scholar]
  20. Scott P. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol. 1991 Nov 1;147(9):3149–3155. [PubMed] [Google Scholar]
  21. Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
  22. Vercelli D., Geha R. S. Regulation of IgE synthesis in humans: a tale of two signals. J Allergy Clin Immunol. 1991 Sep;88(3 Pt 1):285–295. doi: 10.1016/0091-6749(91)90087-5. [DOI] [PubMed] [Google Scholar]
  23. Vercelli D., Jabara H. H., Lauener R. P., Geha R. S. IL-4 inhibits the synthesis of IFN-gamma and induces the synthesis of IgE in human mixed lymphocyte cultures. J Immunol. 1990 Jan 15;144(2):570–573. [PubMed] [Google Scholar]
  24. Wolf S. F., Temple P. A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R. M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed] [Google Scholar]
  25. Wu C. Y., Sarfati M., Heusser C., Fournier S., Rubio-Trujillo M., Peleman R., Delespesse G. Glucocorticoids increase the synthesis of immunoglobulin E by interleukin 4-stimulated human lymphocytes. J Clin Invest. 1991 Mar;87(3):870–877. doi: 10.1172/JCI115092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Zhang K., Clark E. A., Saxon A. CD40 stimulation provides an IFN-gamma-independent and IL-4-dependent differentiation signal directly to human B cells for IgE production. J Immunol. 1991 Mar 15;146(6):1836–1842. [PubMed] [Google Scholar]

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