Prostaglandin I2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

Abstract

BackgroundProstaglandin I2 (PGI2), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI2 signaling suppressed Th1 and Th2 immune responses, the role of PGI2 in Th17 differentiation is not known.Methodology/Principal FindingsIn mouse CD4+CD62L+ naïve T cell culture, the PGI2 analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI2 receptor IP signaling. In mouse bone marrow-derived CD11c+ dendritic cells (BMDCs), PGI2 analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI2 promotes in vivo Th17 responses.ConclusionThe preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI2 and its analogs are commonly used to treat human pulmonary hypertension.

Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension

“…These latter studies also demonstrated that T cell infiltration is reduced in aortae from IL-17 −/− mice after Ang II infusion 24 . The mechanisms by which IL-17 modulates BP are not completely understood though some studies suggest IL-17 mediates Ang II-dependent hypertension by activating the RhoA/Rho-kinase 25 and prostaglandin I 2 26 pathways resulting in superoxide production 11 . Other studies implicate involvement of TNF production by Th17 cells and TNF-dependent signaling via p38/MAP kinase 27 .…”

Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives TH17 Cell Development during Hepatitis C Virus Infection

“…T H 17 cells are newer members of T H cell family and are distinct from T H 1 and T H 2, being characterized by their ability to produce specific cytokines such as IL-17A, IL-17F, IL-22, and CCL20. The conditions for the differentiation of T H 17 cells remains unclear, but the ratio of IL-12/IL-23 produced by monocytes may play a pivotal role in several disease models (40). IL-23 was essential for development of pathogenic T H 17 cells in autoimmune inflammation as indicated by undetectable T H 17 cells in IL-23p19 deficient mice (41,42).…”

PGI2 as a regulator of CD4+ subset differentiation and function

“…IL-23 is secreted by DCs, and promotes maturation of the Th17 cell phenotype [31]. As mentioned earlier, PGI 2 significantly decreased expression of IL-12 by BMDCs in a dose-dependent manner following LPS stimulation; however, PGI 2 had no effect on the expression of IL-23 by these cells [32]. Therefore, the ratio of IL-12 to IL-23 in the microenvironment heavily favors Th17 cell differentiation.…”