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. 1995 Aug;63(8):3101–3105. doi: 10.1128/iai.63.8.3101-3105.1995

Role of Ca2+ in prostaglandin E2-induced T-lymphocyte proliferative suppression in sepsis.

M A Choudhry 1, S Ahmad 1, M M Sayeed 1
PMCID: PMC173423  PMID: 7622237

Abstract

Prostaglandin E2 (PGE2) has been known to modulate immune responses by inhibiting T-cell activation following hemorrhagic and traumatic injury. Recently, we documented a sepsis-related depression in concanavalin A (ConA)-induced T-cell proliferation and intracellular Ca2+ (Ca2+i) mobilization. The present study evaluated the potential role of PGE2 in the sepsis-related attenuation in Ca2+ signaling and proliferation in T cells. Sepsis was induced in rats by implanting into their abdomen fecal pellets containing Escherichia coli (150 CFU) and Bacteroides fragilis (10(4) CFU). A group of rats implanted with septic pellets were treated with indomethacin at three consecutive time points. Levels of PGE2 in blood were measured with a radioimmunoassay kit. ConA-induced [Ca2+]i mobilization in T cells obtained from indomethacin-treated and untreated rats was measured with Fura-2 and microfluorometry. We observed a 10-fold increase in PGE2 levels in the circulation of septic rats compared with levels in rats implanted with bacterium-free sterilized pellets. The proliferative response and Ca2+i mobilization were significantly depressed in T cells obtained from septic rats 48 h after implantations compared with those in rats implanted with sterile pellets. However, treatment of rats with the cyclooxygenase inhibitor indomethacin prevented the sepsis-related depression in ConA-induced T-cell Ca2+i mobilization as well as proliferation. Further, incubation of T cells from nonimplanted control rats with PGE2 resulted in a substantial depression in both T-cell proliferation and Ca2+i mobilization. The restoration of T-cell proliferation and Ca2+ signaling after indomethacin treatment of septic rats and the depression in the mitogen responsiveness in T cells previously exposed to PGE2 suggest that the PGE2 does play a significant role in the modulation of T-cell responses in septic rats and that such PGE2-induced suppression in T-cell activation is likely due to an attenuation in Ca2+ signaling.

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Selected References

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  1. Ahmad S., Karlstad M. D., Choudhry M. A., Sayeed M. M. Sepsis-induced myofibrillar protein catabolism in rat skeletal muscle. Life Sci. 1994;55(18):1383–1391. doi: 10.1016/0024-3205(94)00752-7. [DOI] [PubMed] [Google Scholar]
  2. Altman A., Coggeshall K. M., Mustelin T. Molecular events mediating T cell activation. Adv Immunol. 1990;48:227–360. doi: 10.1016/s0065-2776(08)60756-7. [DOI] [PubMed] [Google Scholar]
  3. Anastassiou E. D., Paliogianni F., Balow J. P., Yamada H., Boumpas D. T. Prostaglandin E2 and other cyclic AMP-elevating agents modulate IL-2 and IL-2R alpha gene expression at multiple levels. J Immunol. 1992 May 1;148(9):2845–2852. [PubMed] [Google Scholar]
  4. Antonacci A. C., Calvano S. E., Reaves L. E., Prajapati A., Bockman R., Welte K., Mertelsmann R., Gupta S., Good R. A., Shires G. T. Autologous and allogeneic mixed-lymphocyte responses following thermal injury in man: the immunomodulatory effects of interleukin 1, interleukin 2, and a prostaglandin inhibitor, WY-18251. Clin Immunol Immunopathol. 1984 Feb;30(2):304–320. doi: 10.1016/0090-1229(84)90064-3. [DOI] [PubMed] [Google Scholar]
  5. Baker P. E., Fahey J. V., Munck A. Prostaglandin inhibition of T-cell proliferation is mediated at two levels. Cell Immunol. 1981 Jun;61(1):52–61. doi: 10.1016/0008-8749(81)90353-1. [DOI] [PubMed] [Google Scholar]
  6. Bauman G. P., Bartik M. M., Brooks W. H., Roszman T. L. Induction of cAMP-dependent protein kinase (PKA) activity in T cells after stimulation of the prostaglandin E2 or the beta-adrenergic receptors: relationship between PKA activity and inhibition of anti-CD3 monoclonal antibody-induced T cell proliferation. Cell Immunol. 1994 Oct 1;158(1):182–194. doi: 10.1006/cimm.1994.1266. [DOI] [PubMed] [Google Scholar]
  7. Bhattacharyya J., Thompson K. D., Sayeed M. M. Skeletal muscle Ca2+ flux and catabolic response during sepsis. Am J Physiol. 1993 Sep;265(3 Pt 2):R487–R493. doi: 10.1152/ajpregu.1993.265.3.R487. [DOI] [PubMed] [Google Scholar]
  8. Bottoms G. D., Adams H. R. Involvement of prostaglandins and leukotrienes in the pathogenesis of endotoxemia and sepsis. J Am Vet Med Assoc. 1992 Jun 15;200(12):1842–1848. [PubMed] [Google Scholar]
  9. Chen D., Rothenberg E. V. Interleukin 2 transcription factors as molecular targets of cAMP inhibition: delayed inhibition kinetics and combinatorial transcription roles. J Exp Med. 1994 Mar 1;179(3):931–942. doi: 10.1084/jem.179.3.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chouaib S., Robb R. J., Welte K., Dupont B. Analysis of prostaglandin E2 effect on T lymphocyte activation. Abrogation of prostaglandin E2 inhibitory effect by the tumor promotor 12.0 tetradecanoyl phorbol-13 acetate. J Clin Invest. 1987 Aug;80(2):333–340. doi: 10.1172/JCI113077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Choudhry M. A., Ahmad S., Thompson K. D., Sayeed M. M. T-lymphocyte Ca2+ signalling and proliferative responses during sepsis. Shock. 1994 Jun;1(6):466–471. doi: 10.1097/00024382-199406000-00012. [DOI] [PubMed] [Google Scholar]
  12. Clipstone N. A., Crabtree G. R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992 Jun 25;357(6380):695–697. doi: 10.1038/357695a0. [DOI] [PubMed] [Google Scholar]
  13. Crabtree G. R. Contingent genetic regulatory events in T lymphocyte activation. Science. 1989 Jan 20;243(4889):355–361. doi: 10.1126/science.2783497. [DOI] [PubMed] [Google Scholar]
  14. Ertel W., Morrison M. H., Meldrum D. R., Ayala A., Chaudry I. H. Ibuprofen restores cellular immunity and decreases susceptibility to sepsis following hemorrhage. J Surg Res. 1992 Jul;53(1):55–61. doi: 10.1016/0022-4804(92)90013-p. [DOI] [PubMed] [Google Scholar]
  15. Faist E., Ertel W., Cohnert T., Huber P., Inthorn D., Heberer G. Immunoprotective effects of cyclooxygenase inhibition in patients with major surgical trauma. J Trauma. 1990 Jan;30(1):8–18. doi: 10.1097/00005373-199001000-00002. [DOI] [PubMed] [Google Scholar]
  16. Faist E., Mewes A., Baker C. C., Strasser T., Alkan S. S., Rieber P., Heberer G. Prostaglandin E2 (PGE2)-dependent suppression of interleukin alpha (IL-2) production in patients with major trauma. J Trauma. 1987 Aug;27(8):837–848. doi: 10.1097/00005373-198708000-00001. [DOI] [PubMed] [Google Scholar]
  17. Faist E., Schinkel C., Zimmer S., Kremer J. P., Von Donnersmarck G. H., Schildberg F. W. Inadequate interleukin-2 synthesis and interleukin-2 messenger expression following thermal and mechanical trauma in humans is caused by defective transmembrane signalling. J Trauma. 1993 Jun;34(6):846–854. doi: 10.1097/00005373-199306000-00016. [DOI] [PubMed] [Google Scholar]
  18. Goodwin J. S., Bankhurst A. D., Messner R. P. Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell. J Exp Med. 1977 Dec 1;146(6):1719–1734. doi: 10.1084/jem.146.6.1719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  21. Hansbrough J. F., Peterson V., Kortz E., Piacentine J. Postburn immunosuppression in an animal model: monocyte dysfunction induced by burned tissue. Surgery. 1983 Mar;93(3):415–423. [PubMed] [Google Scholar]
  22. Hansbrough J., Peterson V., Zapata-Sirvent R., Claman H. N. Postburn immunosuppression in an animal model. II. Restoration of cell-mediated immunity by immunomodulating drugs. Surgery. 1984 Mar;95(3):290–296. [PubMed] [Google Scholar]
  23. Hoyt D. B., Junger W. G., Loomis W. H., Liu F. C. Effects of trauma on immune cell function: impairment of intracellular calcium signaling. Shock. 1994 Jul;2(1):23–28. doi: 10.1097/00024382-199407000-00005. [DOI] [PubMed] [Google Scholar]
  24. Imboden J. B., Weiss A. The T-cell antigen receptor regulates sustained increases in cytoplasmic free Ca2+ through extracellular Ca2+ influx and ongoing intracellular Ca2+ mobilization. Biochem J. 1987 Nov 1;247(3):695–700. doi: 10.1042/bj2470695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Lerner A., Jacobson B., Miller R. A. Cyclic AMP concentrations modulate both calcium flux and hydrolysis of phosphatidylinositol phosphates in mouse T lymphocytes. J Immunol. 1988 Feb 1;140(3):936–940. [PubMed] [Google Scholar]
  28. Lingk D. S., Chan M. A., Gelfand E. W. Increased cyclic adenosine monophosphate levels block progression but not initiation of human T cell proliferation. J Immunol. 1990 Jul 15;145(2):449–455. [PubMed] [Google Scholar]
  29. Mathieu J., Masson I., Chancerelle Y., Chanaud B., Strazlko S., De Sousa M., Kergonou J. F., Giroud J. P., Florentin I. Restoration of postburn impaired lymphocyte responsiveness by nonsteroidal anti-inflammatory drugs is independent of prostaglandin E2 inhibition. J Leukoc Biol. 1994 Jan;55(1):64–72. doi: 10.1002/jlb.55.1.64. [DOI] [PubMed] [Google Scholar]
  30. Minakuchi R., Wacholtz M. C., Davis L. S., Lipsky P. E. Delineation of the mechanism of inhibition of human T cell activation by PGE2. J Immunol. 1990 Oct 15;145(8):2616–2625. [PubMed] [Google Scholar]
  31. Mustelin T., Coggeshall K. M., Isakov N., Altman A. T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation. Science. 1990 Mar 30;247(4950):1584–1587. doi: 10.1126/science.2138816. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Ninnemann J. L., Stockland A. E. Participation of prostaglandin E in immunosuppression following thermal injury. J Trauma. 1984 Mar;24(3):201–207. doi: 10.1097/00005373-198403000-00003. [DOI] [PubMed] [Google Scholar]
  34. Paliogianni F., Kincaid R. L., Boumpas D. T. Prostaglandin E2 and other cyclic AMP elevating agents inhibit interleukin 2 gene transcription by counteracting calcineurin-dependent pathways. J Exp Med. 1993 Nov 1;178(5):1813–1817. doi: 10.1084/jem.178.5.1813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Powrie F., Coffman R. L. Cytokine regulation of T-cell function: potential for therapeutic intervention. Immunol Today. 1993 Jun;14(6):270–274. doi: 10.1016/0167-5699(93)90044-L. [DOI] [PubMed] [Google Scholar]
  36. RAPAPORT F. T., CONVERSE J. M., HORN L., BALLANTYNE D. L., Jr, MULHOLLAND J. H. ALTERED REACTIVITY OF SKIN HOMOGRAFTS IN SEVERE THERMAL INJURY. Ann Surg. 1964 Mar;159:390–395. doi: 10.1097/00000658-196403000-00010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rincón M., Tugores A., López-Rivas A., Silva A., Alonso M., De Landázuri M. O., López-Botet M. Prostaglandin E2 and the increase of intracellular cAMP inhibit the expression of interleukin 2 receptors in human T cells. Eur J Immunol. 1988 Nov;18(11):1791–1796. doi: 10.1002/eji.1830181121. [DOI] [PubMed] [Google Scholar]
  38. Stephan R. N., Conrad P. J., Saizawa M., Dean R. E., Chaudry I. H. Prostaglandin E2 depresses antigen-presenting cell function of peritoneal macrophages. J Surg Res. 1988 Jun;44(6):733–739. doi: 10.1016/0022-4804(88)90108-4. [DOI] [PubMed] [Google Scholar]
  39. Teodorczyk-Injeyan J. A., Sparkes B. G., Peters W. J., Gerry K., Falk R. E. Prostaglandin E-related impaired expression of interleukin-2 receptor in the burn patient. Adv Prostaglandin Thromboxane Leukot Res. 1987;17A:147–150. [PubMed] [Google Scholar]
  40. Tsien R. Y., Pozzan T., Rink T. J. T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature. 1982 Jan 7;295(5844):68–71. doi: 10.1038/295068a0. [DOI] [PubMed] [Google Scholar]
  41. Ullman K. S., Northrop J. P., Verweij C. L., Crabtree G. R. Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. Annu Rev Immunol. 1990;8:421–452. doi: 10.1146/annurev.iy.08.040190.002225. [DOI] [PubMed] [Google Scholar]
  42. Wacholtz M. C., Lipsky P. E. Anti-CD3-stimulated Ca2+ signal in individual human peripheral T cells. Activation correlates with a sustained increase in intracellular Ca2+1. J Immunol. 1993 Jun 15;150(12):5338–5349. [PubMed] [Google Scholar]
  43. Wolfe J. H., Wu A. V., O'Connor N. E., Saporoschetz I., Mannick J. A. Anergy, immunosuppressive serum, and impaired lymphocyte blastogenesis in burn patients. Arch Surg. 1982 Oct;117(10):1266–1271. doi: 10.1001/archsurg.1982.01380340002002. [DOI] [PubMed] [Google Scholar]

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