Interferon-gamma (IFN-γ) and prostaglandin E2 (PGE2) regulate differently IL-12 production in human intestinal lamina propria mononuclear cells (LPMC)

Abstract

SUMMARYIL-12 modulates Th1 immune response during chronic colitis. Mechanisms regulating IL-12 synthesis in human intestine are poorly understood. The aim of this study was to investigate the effect of IFN-g and PGE 2 on lipopolysaccharide (LPS)-stimulated LPMC IL-12 production. Normal LPMC cultures were run in the presence or absence of IFN-g and/or PGE 2 before LPS stimulation. 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 either unstimulated or LPS-stimulated LPMC cultures. In contrast, LPMC released IL-8 (650 6 125 pg/ml) and IL-10 (75 6 25 pg/ml) in response to LPS. Treatment of LPMC with IFN-g facilitated LPS-stimulated IL-12, whereas it completely abrogated IL-10 production. IL-12 release by LPMC stimulated with IFN-g and LPS was signi®cantly inhibited by exogenous IL-10. The addition of PGE 2 to IFN-g-treated LPMC cultures inhibited in a dose-dependent manner LPS-induced IL-12 secretion. Furthermore, IL-12 was detectable (85 6 25 pg/ml) in the supernatants of LPMC cultures treated with indomethacin and LPS. In contrast to the effect on IL-12, PGE 2 signi®cantly 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 simpli®ed model of LPS tolerance, we ®nally 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-g and PGE 2 modulate differently the LPMC responsiveness to LPS in terms of IL-12 synthesis.

An Herbal Medicine Orengedokuto Prevents Indomethacin-Induced Enteropathy

“…Lamina propria is a major site of mucosal PGE2 production, which has recently been reported to lead to production of IL-10, a key cytokine involved in mucosal tolerance. 5,6,22,24) In agreement with previous studies, 5,24) we observed that LPMC produced PGE2 and IL-10 spontaneously (Fig. 12A-a and c).…”

“…[1][2][3][4] PGE2 enhances interleukin 10 (IL-10) synthesis and modulates the intestinal immune response to dietary antigen. 5,6) The breakdown of systemic tolerance to luminal antigen is reportedly involved in the development of indomethacin-induced enteropathy. 7) Indomethacin is one of the non-steroidal anti-inflammatory drugs (NSAIDs) that reduce PGE2 production via inhibition of the cyclooxygenases (COXs) 2) , COX-1 and COX-2.…”

Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma

“…The levels of IL-8 and Foxp3 expression were correlated per single cell basis (Fig. 6E) 29 The data suggests that in addition to macrophages, other cells may be important producers of IL-8 in the colon mucosa. In line with this possibility, to our surprise, we have shown that the levels of IL-8 are dramatically higher in Treg cells than the Treg-depleted mononuclear cells (containing macrophages) in the microenvironments of colitis and colon cancer.…”

Regulation of IL-12 p40 Promoter Activity in Primary Human Monocytes: Roles of NF-κB, CCAAT/Enhancer-Binding Protein β, and PU.1 and Identification of a Novel Repressor Element (GA-12) That Responds to IL-4 and Prostaglandin E2

“…A footprint over a purine-rich sequence at Ϫ155 observed only in resting cells was caused by a specific protein complex, denoted GATA sequence in the IL-12 promoter (GA-12) 3 binding protein (GAP-12), thereby repressing inducible IL-12 p40 gene transcription in monocytes. Interestingly, GAP-12 binding to this site was enhanced by IL-4 and PGE 2 , which have been previously described as potent inhibitors of IL-12 expression (21)(22)(23)(24)(25). Our data suggest a model in which the stimulation of monocytes and macrophages with bacterial cell wall components such as LPS leads to the displacement of the GAP-12 repressor and subsequently to the binding of activating transcription factors such as p50/p65, C/EBP␤, and PU.1.…”