Prostaglandin I2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis
by Weisong Zhou, Dustin R. Dowell, Matthew M. Huckabee, Dawn C. Newcomb, Madison G. Boswell, Kasia Goleniewska, Matthew T. Lotz, Shinji Toki, Huiyong Yin, Songyi Yao, Chandramohan Natarajan, Pingsheng Wu, Subramaniam Sriram, Richard M. Breyer, Garret A. FitzGerald, R. Stokes Peebles
Prostaglandin 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.
In 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.
The 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.
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Syndicated from:PLoS ONE
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