Prostaglandin I2 signaling drives Th17 differentiation and exacerbates experimental autoimmune encephalomyelitis

• Published in: PloS one 2012-05, Vol.7 (5), p.e33518-e33518
• Main Authors: Zhou, Weisong, Dowell, Dustin R, Huckabee, Matthew M, Newcomb, Dawn C, Boswell, Madison G, Goleniewska, Kasia, Lotz, Matthew T, Toki, Shinji, Yin, Huiyong, Yao, Songyi, Natarajan, Chandramohan, Wu, Pingsheng, Sriram, Subramaniam, Breyer, Richard M, Fitzgerald, Garret A, Peebles, Jr, R Stokes
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Analogs; Animals; Antineoplastic Agents - immunology; Antineoplastic Agents - pharmacology; Arthritis; Biology; Bone marrow; CD11c antigen; CD4 antigen; Cell culture; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cells, Cultured; Cords; Critical care; Cytokines; Dendritic cells; Differentiation; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Epoprostenol - analogs & derivatives; Epoprostenol - genetics; Epoprostenol - immunology; Epoprostenol - pharmacology; Experimental allergic encephalomyelitis; Female; Helper cells; Humans; Hypertension; Iloprost - immunology; Iloprost - pharmacology; Immune response; Infections; Infiltration; Inflammation; Inflammatory bowel disease; Interleukin 12; Interleukin 22; Interleukin 23; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-17 - genetics; Interleukin-17 - immunology; Interleukin-23 - genetics; Interleukin-23 - immunology; L-selectin; Leukocytes (mononuclear); Lymphocytes; Lymphocytes T; Medical treatment; Medicine; Mice; Mice, Inbred BALB C; Mice, Knockout; Multiple sclerosis; Mycoplasma pneumoniae; Neurology; Neutrophils; Physicians; Platelet Aggregation Inhibitors - immunology; Platelet Aggregation Inhibitors - pharmacology; Pneumonia; Prostacyclin; Pulmonary hypertension; Receptors, Epoprostenol - genetics; Receptors, Epoprostenol - immunology; Rodents; Signaling; Spinal Cord - immunology; Spinal Cord - pathology; Stem cells; Th17 Cells - immunology; Th17 Cells - pathology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033518

Prostaglandin I(2) (PGI(2)), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI(2) signaling suppressed Th1 and Th2 immune responses, the role of PGI(2) in Th17 differentiation is not known. In mouse CD4(+)CD62L(+) naïve T cell culture, the PGI(2) 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 PGI(2) receptor IP signaling. In mouse bone marrow-derived CD11c(+) dendritic cells (BMDCs), PGI(2) 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 PGI(2) promotes in vivo Th17 responses. The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI(2) and its analogs are commonly used to treat human pulmonary hypertension.