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Comparative study of the endotoxemia and endotoxin tolerance on the production of th cytokines and macrophage interleukin-6: Differential regulation of indomethacin

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Abstract

Endotoxin tolerance reduces the capacity of monocytes to produce proinflammatory cytokines, results in cellular immune paralysis, and down-regulates the production of helper T (Th)1 type cytokines with a shift toward a Th2 cytokine response. Prostaglandin (PG)E2 in the immune system also results in macrophage inactivation and the suppression of Th1 activation and the enhancement of Th2 activation. However, the inhibitory effects of PGE2 on the altered polarization of the Th cell and macrophage interleukin (IL)-6 production characterized in part by cellular immune paralysis in a state of endotoxin tolerance is unclear. This study was undertaken, using indomethacin, to investigate the role of endogenous PGE2 on the Th cytokines and macrophage IL-6 production in a state of endotoxin tolerance compared to those with endotoxemia mice, wherein, in this latter case, the increased production of proinflammatory cytokines and PGE2 is exhibited. Endotoxemia was induced by injection of lipopolysaccharide (LPS; 10 mg/kg in saline)i.p. once in BALB/c mice, and endotoxin tolerance was induced by pretreatment with LPS (1 mg/kg in saline) injectedi.p. daily for two consecutive days and then with LPS 10 mg/kg on day 4. Splenocytes or macrophages were obtained from endotoxemia and endotoxin tolerance models pretreated with indomethacin, and then cytokine production was induced by Con A-stimulated splenocytes for the Th cytokine assays and LPS-stimulated macrophages for the IL-6 assay. Our results showed that endotoxemia led to significantly reduced IL-2 and IL-4 production, to significantly increased IL-6 production, whereas interferon (IFN)-γ production was not affected. Indomethacin in the case of endotoxemia markedly attenuated IFN-γ and IL-6 production and didnt reverse IL-2 and IL-4 production. Endotoxin tolerance resulted in the significantly reduced production of IL-2 and IFN-y and the significantly increased production of IL-4 and IL-6. Indomethacin in endotoxin tolerance greatly augmented IL-2 production, significantly decreased IL-4 production, and slightly attenuated IL-6 production. These findings indicate that endogenous PGE2 may mediate the suppressed Th1 type immune response, with a shift toward a Th2 cytokine response in a state of endotoxin tolerance, whereas endotoxemia may be regulated differentially. Also, endogenous PGE2 may mediate macrophage IL-6 production in the case of endotoxemia to a greater extent than in the case of endotoxin tolerance.

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References

  • Abbas, A. K., Murphy, K. M. and Sher, A., Functional diversity of helper T lymphocytes.Nature, 383, 787–793 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Barton, B. E., IL-6-like cytokines and cancer cachexia: consequences of chronic inflammation.Immunol. Res. 23 (1), 41–58 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Betz, M. and Fox, B., Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines.J. Immunol., 146, 108–113 (1991).

    PubMed  CAS  Google Scholar 

  • Castro, A., Bemer, V., Nobrega, A., Coutinho, A. and Truffa-Bachi, P., Administration to mice of endotoxin from gram-negative bacteria leads to activation and apoptosis of T lymphocytes.Eur. J. Immunol., 28 488–495 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Chai, Z., Gatti, S., Toniatti, C., Poli, V. and Bartfai, T., Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1β: a study on IL-6-deficient mice.J. Exp. Med., 183, 311–316 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Chemo, A., Fraifeld, V., Adramovich, L., Sod-Moriah, U. A. and Kaplanski, J., Tolerance to lipopolysaccharide is not related to the ability of the hypothalamus to produce prostaglandin E2.Life Sci., 61 (8), 813–818 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Chen, H., Halushka, P. V. and Cook, J. A., Endotoxin tolerance: effects on lethality and macrophage thromboxane (B2) and interleukin 6 production.Shock, 1, 366–371 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Choudhry, M. A., Ahmad, S. Ahmad, Z. and Sayeed, M. M., Prostaglandin E2 down-regulation of T-cell IL-2 production is independent of IL-10 during gram-negative sepsis.Immunol. Lett. 67 (2) 125–130 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Choudhry, M. A., Ahmad, S. and Sayeed, M. M., Role of Ca2+; in prostaglandin E2-induced T-lymphocyte proliferative suppression in sepsis.Infect. Immun., 63 (8), 3101 (1995).

    PubMed  CAS  Google Scholar 

  • Coffman, R. L. and Carty, J., A T cell activity that enhances polyclonal IgE production and its inhibition by interferon.J. Immunol., 136, 949–954 (1986).

    PubMed  CAS  Google Scholar 

  • Diao, H., Kohanawa, M. Y., Nakajima, H., Sato, Y., Minagawa, T. and Nakane, A. Y., Lipopolysaccharide triggers invasive streptococcal disease in mice through a tumor necrosis factor-alpha-dependent mechanism.Immunology, 105 (3), 344–349 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Dinarello, C. A., Cannon, J. G., Mancilla, J., Bishai, I., Lees, J. and Coceani, F., lnterleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells.Brain Res., 562, 199–206 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Erroi, A., Fantuzzi, G., Mengozzi, M., Sironi, M., Orencole, S. F., Clark, B. D., Dinarello, C. A., Isetta, A., Gnocchi, P., Giovarelli, M., et al., Differential regulation of cytokine production in lipopolysaccharide tolerance in mice.Infect. Immun., 61 (10), 4356–4359 (1993).

    PubMed  CAS  Google Scholar 

  • Hafenrichter, D. G., Roland, C. R., Mangino, Mj. and Flye, M. W., The Kupffer cell in endotoxin tolerance: mechanisms of protection against lethal endotoxemia.Shock 2 (4), 251–256 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Harizi, H., Juzan, M., Pitard, V., Moreau, J. F. and Gualde, N., Cycloxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulateds dendritic cell functions.J. Immunol, 168 (5), 2255–2263 (2002).

    PubMed  CAS  Google Scholar 

  • Hinson, R. M., Williams, J. A. and Shacter, E., Elevated inter-leukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.Proc. Natl. Acad. Sci. U.S.A., 93, 4885–4890 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Howells, G., Pham, P., Taylor, D., Foxwell, B. and Feldmann, M., Interleukin 4 induces interleukin 6 production by endothelial cells: synergy with interferon-gamma.Eur. J. Im-munol. 21 (1), 97–101 (1991).

    Article  CAS  Google Scholar 

  • Howes, E. L., Jr, Goldyne, M. E., Perez, H. D., Goldstein, I. M. and Rosenbaum, J. T., Lipopolysaccharide tolerance inhibits eye inflammation. I. Reduced immune complex or lipopolysaccharide effects.Arch. Ophthalmol., 103 (2), 257–260 (1985).

    PubMed  CAS  Google Scholar 

  • Iwahashi, H., Takeshita, A and Hanazawa, S., Prostaglandin E2 stimulates AP-1-mediated CD14 expression in mouse macrophages via cyclic AMP-dependent protein kinas.A. J. Immunology, 164, 5403–5408 (2000).

    CAS  Google Scholar 

  • Karp, C. L. M., Wysocka, M., Ma, X., Marovich, M., Factor, R. E., Nutman, T., Armant, M., Wahl, L., Cuomo, P. and Trinchieri, G., Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance.Eur. J. Immunol., 28, 3128 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Kaur, K., Harris, S. G., Padilla, J., Graf, B. A. and Phipps, R. P., Prostaglandin E2 as a modulator of lymphocyte mediated inflammatory and humoral responses.Adv. Exp. Med. Biol., 469, 409–411 (1999).

    PubMed  CAS  Google Scholar 

  • Lauw, F. N., Ten Hove, T., Dekkers, P. E. P. D. E. Jonge, E., Van Deventer, S. J. H. and Van der Poll, T., Reduced Th1, but not Th2, cytokine production by lymphocytes afterin vivo exposure of healthy subjects to endotoxin.Infection and immunity, 68 (3), 1014–1018 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Lehner, M. D., Ittner, J., Bundschuh, D. S., van Rooilen, N., Wendel, A. and Hartung, T., Improved innate immunity of endotoxin-tolerant mice increases resistance t.Salmonella enterica Serovar Typhimurium infection despite attenuated cytokine response.Infection and Immunity, 69 (1), 463–471 (2001).

    CAS  Google Scholar 

  • Li, M. H., Seatter, S. C., Manthei, R., Bubrick, M. and West, M. A., Macrophage endotoxin tolerance: effect of TNF or endotoxin pretreatment.J. Surg. Res., 57 (1), 85–92 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Menetrier-Caux, C., Bain, C., Favrot, M. C., Due, A. and Blay, J. Y., Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by monocytes.Br. J. Cancer, 79 (1), 119 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Meyer, T. A., Noguchi, Y., Ogle, C. K., Tiao, G., Wang, J. J., Fisher, J. E. and Hasselgren, P. O., Endotoxin stimulates interleukin-6 production in intestinal epithelial cells. A synergistic effect with prostaglandin E2.Arch. Surg., 129 (12), 1290–1295 (1994).

    PubMed  CAS  Google Scholar 

  • Minakuchi, R., Wacholtz, M., Davis, L. and Lipsky, P., Delineation of the mechanism of inhibition of human T cell activation by PGE2.J. Immunol., 145, 2616–2625 (1990).

    PubMed  CAS  Google Scholar 

  • Morrison, D. C. and Ryan, J. L., Bacterial endotoxins and host immune responses.Adv. Immunol., 28, 293–304 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Munoz, C., Carlet, J., Fitting, C., Misset, B., Bleriot, J. P. and Cavaillon, J. M., Dysregulation ofin vitro cytokine production by monocytes during sepsis.J. Clin. Investig., 88, 1747–1754 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Mureille, E. and Leo, O., Revising the Th1/Th2 paradigm.Scand. J. Immunol., 47, 1–9 (1998).

    Google Scholar 

  • Perez-Santos, J. L and Talamas-Rohana, P., In vitro indo-methacin administration upregulates interleukin-12 production and polarizes the immune response toward a Th1 type in susceptible BALB/c mice infected with Leishmania mexicana.Parasite Immunol. 23 (11) 599–606 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Rogers, T. S., Halushka, P. V., Wise, W. C. and Cook, J. A., Differential alteration of lipoxygenase and cyclooxygenase metabolism by rat peritoneal macrophages induced by endotoxin tolerance.Prostaglandins, 31 (4), 639–650 (1986).

    Article  PubMed  CAS  Google Scholar 

  • Roper, R., Brown, D., and Phipps, R. Prostagalndin E2 promotes B lymphocyte Ig isotype switching to IgE.J. Immunol., 154, 162–170 (1995).

    PubMed  CAS  Google Scholar 

  • Schade, F. U., Flash, R., Flohe, S., Majetschak, M., Kreuzfelder, E., Domihguez-Femandez, E., Borgermann, J., Reuter, M. and Obertacke, U., Endotoxin tolerance.In Endotoxin in health and disease. Brade, H., Opal, S. M., Vogel, S. N. and Morrison, D. C., eds Marcel Dekker, New York, p 50 (1999).

    Google Scholar 

  • Swain, S. L., Weinberg, A. D., English, M. and Huston, G., IL-4 directs the development of Th2-like helper effectors.J. Immunol. 145 (11), 3796–806 (1990).

    PubMed  CAS  Google Scholar 

  • van der pouw Kraan, T. L., Boeije, L., Smeenk, R., Wijdenes, J. and Aarden, L., Proataglandin-e2 is a potent inhibitor of human interleukin 12 production.J. Exp. Med., 181, 775–779 (1995).

    Article  PubMed  Google Scholar 

  • Volk, H. D., Reinke, P. and Docke, W. D., Clinical aspects: from systemic inflammation to “immunoparalysis.”Chem. Immunol., 74, 162 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Williams, J. A. and Shacter, E., Regulation of macrophage cytokine production by prostaglandin E2: distinct roles of cyclooxygenase-1 and 2.J. Biol. Chem., 272 (41), 25693–699 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Wysocka, M., Robertson, S., Riemann, H., Caamano, J., Hunter, C., Mackiewicz, A., montaner, L. J., Trinchieri, G. and Karp, C. L., IL-12 suppression during experimental endotoxin tolerance: Dendritic cell loss and macrophage hyporespon-siveness.J. Immunol., 166, 7504–7513 (2001).

    PubMed  CAS  Google Scholar 

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  1. College of Science and Engineering, Woosuk University, 565-701, Samrae-Up, Jeonbuk, Korea

    Byeong Suk Chae

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Chae, B.S. Comparative study of the endotoxemia and endotoxin tolerance on the production of th cytokines and macrophage interleukin-6: Differential regulation of indomethacin. Arch Pharm Res 25, 910–916 (2002). https://doi.org/10.1007/BF02977013

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