PGE2 and IL-27: novel pro-inflammatory mechanisms involving dendritic cells and Tr1 cells

Abstract

Abstract Interleukin-27 (p28/EBI3) is an immunomodulatory cytokine expressed by activated antigen presenting cells. Although first discovered to be involved in Th1 cell differentiation, further studies demonstrated the immunosuppressive functions of IL-27 including the inhibition of Th17 cell development and the induction of type 1 regulatory T cells (Tr1) and exhausted CD4+ T cells. The anti-inflammatory effects of IL-27 have been demonstrated in vivo in murine models of parasitic infections and autoimmune disease models such as experimental autoimmune encephalomyelitis and inflammatory bowel disease (IBD). We previously detailed the pro-inflammatory effects of PGE2 in collagen-induced arthritis and IBD through stimulation of IL-23 production leading to development of Th17 cells. Here we describe novel pro-inflammatory functions of PGE2, i.e. inhibition of IL-27 production by murine bone marrow-derived dendritic cells (DC), inhibition of Tr1 differentiation and of IL-10 production by Tr1 cells. We determined that the effect of PGE2 on IL-27 production in LPS-stimulated DC is mediated through EP2/EP4 receptors, induction of cAMP, and partial inhibition of both IRF1 and IRF3. Furthermore, we found that PGE2 treatment of LPS-stimulated DC reduces IRF1 binding to an essential ISRE site within the p28 promoter. In addition to the effects of IL-27 in DC, we also found that PGE2 directly inhibits IL-27-induced differentiation of Tr1 cells through EP4, and inhibits production of IL-10 by Tr1 cells through EP2/EP4. These studies further describe the pro-inflammatory effects of PGE2 and identify possible new targets for treatment of inflammatory diseases.