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

• Published in: Archives of pharmacal research 2002-12, Vol.25 (6), p.910-916
• Main Author: Chae, Byeong Suk
• Format: Article
• Language: English
• Subjects: Animals; CD4-positive T-lymphocytes; cytokines; Cytokines - biosynthesis; Dinoprostone - antagonists & inhibitors; Dinoprostone - biosynthesis; endotoxemia; Endotoxemia - chemically induced; Endotoxemia - metabolism; endotoxins; Endotoxins - toxicity; Female; immune response; Immune Tolerance - drug effects; indomethacin; Indomethacin - pharmacology; Indomethacin - therapeutic use; interferon-gamma; interleukin-2; interleukin-4; interleukin-6; Interleukin-6 - biosynthesis; lipopolysaccharides; macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred BALB C; monocytes; paralysis; prostaglandins; Spleen - cytology; Spleen - drug effects; Spleen - metabolism; splenocytes; Th1 Cells - drug effects; Th1 Cells - immunology; Th1 Cells - metabolism
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/BF02977013

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.