Interferon-gamma (IFN-gamma) and prostaglandin E-2 (PGE(2)) regulate differently IL-12 production in human intestinal lamina propria mononuclear cells (LPMC)

IL-12 modulates Th1 immune response during chronic colitis. Mechanisms regu lating IL-12 synthesis in human intestine are poorly understood. The aim of this study was to investigate the effect of IFN-gamma and PGE(2) on lipopo lysaccharide (LPS)-stimulated LPMC IL-12 production. Normal LPMC cultures w ere run in the presence or absence of IFN-gamma and/or PGE(2) before LPS st imulation. To examine the role of endogenous PGE(2) on LPS-stimulated IL-12 release, LPMC cultures were added of indomethacin before LPS stimulation. IL-12, IL-10 and IL-8 were measured by ELISA. No IL-12 was detected in eith er unstimulated or LPS-stimulated LPMC cultures. In contrast, LPMC released IL-8 (650 +/- 125 pg/ml) and IL-10 (75 +/- 25 pg/ml) in response to LPS. T reatment of LPMC with IFN-gamma facilitated LPS-stimulated IL-12, whereas i t completely abrogated IL-10 production. IL-12 release by LPMC stimulated w ith IFN-gamma and LPS was significantly inhibited by exogenous IL-10. The a ddition of PGE(2) to IFN-gamma-treated LPMC cultures inhibited in a dose-de pendent manner LPS-induced IL-12 secretion. Furthermore, IL-12 was detectab le (85 +/- 25 pg/ml) in the supernatants of LPMC cultures treated with indo methacin and LPS. Ln contrast to the effect on IL-12, PGE(2) significantly augmented LPS-stimulated LPMC IL-10 production. However, the inhibition of IL-12 by PGE(2) was only partially reversed by anti-IL-10. In a simplified model of LPS tolerance, we finally showed that monocyte-derived macrophages exhibited reduced IL-12 production after repeat LPS stimulation. In these cell cultures, indomethacin abrogated the induction of LPS desensitization. IFN-gamma and PGE2 modulate differently the LPMC responsiveness to LPS in terms of IL-12 synthesis.