Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Feb 1;181(2):775–779. doi: 10.1084/jem.181.2.775

Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production

PMCID: PMC2191857  PMID: 7836930

Abstract

During human immunodeficiency virus infection and allergic diseases, characterized by a dominant T helper (Th) 2 response, overproduction of prostaglandin E2 (PGE2) is observed. In this paper we studied the effect of PGE2 on interleukin (IL)-12 synthesis, because this cytokine has been described to be essential in induction of Th1 responses. IL-12 synthesis was induced in monocytes that were stimulated with Neisseria meningitidis-derived lipopolysaccharide in whole blood cultures. PGE2 almost completely inhibited lipopolysaccharide induced IL-12 production, whereas IL-6 production was only partially inhibited by PGE2. In contrast, the production of IL-10 was approximately twofold enhanced at these conditions. The effects of PGE2 were due to its cAMP- inducing capacity, since they could be mimicked by other cAMP inducers. Recombinant human IL-10 also inhibited IL-12 and IL-6 production. However, the inhibitory effect of PGE2 on IL-12 production was independent of IL-10 since neutralizing anti-IL-10 antibodies were unable to reverse this inhibition. These results suggest that the capacity of an antigen to induce PGE2 synthesis may play a crucial role in the development of either a Th1 or Th2 response.

Full Text

The Full Text of this article is available as a PDF (513.2 KB).

Selected References

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

  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Betz M., Fox B. S. Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J Immunol. 1991 Jan 1;146(1):108–113. [PubMed] [Google Scholar]
  3. Chehimi J., Starr S. E., Frank I., D'Andrea A., Ma X., MacGregor R. R., Sennelier J., Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. doi: 10.1084/jem.179.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Foley P., Kazazi F., Biti R., Sorrell T. C., Cunningham A. L. HIV infection of monocytes inhibits the T-lymphocyte proliferative response to recall antigens, via production of eicosanoids. Immunology. 1992 Mar;75(3):391–397. [PMC free article] [PubMed] [Google Scholar]
  8. Gajewski T. F., Schell S. R., Fitch F. W. Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones. J Immunol. 1990 Jun 1;144(11):4110–4120. [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. Gazzinelli R. T., Hieny S., Wynn T. A., Wolf S., Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115–6119. doi: 10.1073/pnas.90.13.6115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hofmann B., Nishanian P., Nguyen T., Liu M., Fahey J. L. Restoration of T-cell function in HIV infection by reduction of intracellular cAMP levels with adenosine analogues. AIDS. 1993 May;7(5):659–664. doi: 10.1097/00002030-199305000-00008. [DOI] [PubMed] [Google Scholar]
  13. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  14. Jakob T., Huspith B. N., Latchman Y. E., Rycroft R., Brostoff J. Depressed lymphocyte transformation and the role of prostaglandins in atopic dermatitis. Clin Exp Immunol. 1990 Mar;79(3):380–384. doi: 10.1111/j.1365-2249.1990.tb08099.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kammer G. M. The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunol Today. 1988 Jul-Aug;9(7-8):222–229. doi: 10.1016/0167-5699(88)91220-0. [DOI] [PubMed] [Google Scholar]
  16. Leung D. Y., Key L., Steinberg J. J., Young M. C., Von Deck M., Wilkinson R., Geha R. S. Increased in vitro bone resorption by monocytes in the hyper-immunoglobulin E syndrome. J Immunol. 1988 Jan 1;140(1):84–88. [PubMed] [Google Scholar]
  17. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mastino A., Grelli S., Piacentini M., Oliverio S., Favalli C., Perno C. F., Garci E. Correlation between induction of lymphocyte apoptosis and prostaglandin E2 production by macrophages infected with HIV. Cell Immunol. 1993 Nov;152(1):120–130. doi: 10.1006/cimm.1993.1272. [DOI] [PubMed] [Google Scholar]
  19. McKnight A. J., Zimmer G. J., Fogelman I., Wolf S. F., Abbas A. K. Effects of IL-12 on helper T cell-dependent immune responses in vivo. J Immunol. 1994 Mar 1;152(5):2172–2179. [PubMed] [Google Scholar]
  20. Meyaard L., Schuitemaker H., Miedema F. T-cell dysfunction in HIV infection: anergy due to defective antigen-presenting cell function? Immunol Today. 1993 Apr;14(4):161–164. doi: 10.1016/0167-5699(93)90279-T. [DOI] [PubMed] [Google Scholar]
  21. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  22. Muñoz E., Zubiaga A. M., Merrow M., Sauter N. P., Huber B. T. Cholera toxin discriminates between T helper 1 and 2 cells in T cell receptor-mediated activation: role of cAMP in T cell proliferation. J Exp Med. 1990 Jul 1;172(1):95–103. doi: 10.1084/jem.172.1.95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Novak T. J., Rothenberg E. V. cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9353–9357. doi: 10.1073/pnas.87.23.9353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Phipps R. P., Stein S. H., Roper R. L. A new view of prostaglandin E regulation of the immune response. Immunol Today. 1991 Oct;12(10):349–352. doi: 10.1016/0167-5699(91)90064-Z. [DOI] [PubMed] [Google Scholar]
  25. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991 Aug;12(8):256–257. doi: 10.1016/0167-5699(91)90120-I. [DOI] [PubMed] [Google Scholar]
  26. Schindler R., Dinarello C. A. A method for removing interleukin-1- and tumor necrosis factor-inducing substances from bacterial cultures by ultrafiltration with polysulfone. J Immunol Methods. 1989 Jan 17;116(2):159–165. doi: 10.1016/0022-1759(89)90199-3. [DOI] [PubMed] [Google Scholar]
  27. Seder R. A., Gazzinelli R., Sher A., Paul W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188–10192. doi: 10.1073/pnas.90.21.10188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Snijdewint F. G., Kaliński P., Wierenga E. A., Bos J. D., Kapsenberg M. L. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol. 1993 Jun 15;150(12):5321–5329. [PubMed] [Google Scholar]
  29. Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. doi: 10.1016/0167-5699(93)90230-I. [DOI] [PubMed] [Google Scholar]
  31. Van der Pouw-Kraan T., Van Kooten C., Rensink I., Aarden L. Interleukin (IL)-4 production by human T cells: differential regulation of IL-4 vs. IL-2 production. Eur J Immunol. 1992 May;22(5):1237–1241. doi: 10.1002/eji.1830220519. [DOI] [PubMed] [Google Scholar]
  32. 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]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES