title: Prostaglandin I2-IP signalling regulates human Th17 and Treg cell differentiation.
abstract: Prostaglandin I2 (PGI2) is an important immunoregulatory lipid mediator. In this study, we analysed the effects of the PGI2 analogue (Iloprost) on the differentiation of Th17 cells and Tregs from human naïve CD4(+) T cells. PGI2 receptors (IP) are expressed on human naïve CD4(+) T cells. Via IP binding, the PGI2 analogue decreased the proportion of Tregs and Foxp3 mRNA expression but increased the percentage of Th17 cells, RORC mRNA and IL-17A production. The regulatory effects of Iloprost correlated with elevated intracellular cAMP levels. The effects were mimicked by a cAMP agonist (db-cAMP) but attenuated by a protein kinase A inhibitor (H-89). STAT3 and STAT5 signalling play direct and crucial roles in the development of Th17 and Tregs, respectively. The PGI2 analogue enhanced the activation of STAT3 in response to IL-6, whereas it decreased STAT5 activation in response to IL-2. Moreover, db-cAMP imitated the above effects of Iloprost, which were weakened by H-89. These results demonstrate that the PGI2-IP interaction promoted the phosphorylation of STAT3 and reduced the phosphorylation of STAT5, likely via the upregulation of cAMP-PKA signalling, thus facilitated Th17 differentiation and suppressed Treg differentiation. Together with previous results, these data suggest that prostanoids play an important role in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis.
authors.affiliation: Institute of Basic Medicine, Hebei Medical University, Shijiazhuang 050017, PR China.
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.forename: Di
authors.initials: D
authors.lastname: Wen
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.forename: Shengchang
authors.initials: S
authors.lastname: Yang
authors.forename: Xianxian
authors.initials: X
authors.lastname: Jia
authors.forename: Bin
authors.initials: B
authors.lastname: Cong
authors.forename: Chunling
authors.initials: C
authors.lastname: Ma
mesh_terms: D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases; D011464:Epoprostenol / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508717:IL17A protein, human; C508600:IL6 protein, human; D020381:Interleukin-17; D007376:Interleukin-2; D015850:Interleukin-6; D007546:Isoquinolines; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; C539900:RORC protein, human; D044006:Receptors, Epoprostenol; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D013449:Sulfonamides; D003994:Bucladesine; D011464:Epoprostenol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D016285:Iloprost; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Foxp3; Prostaglandin I(2); RORC; Regulatory T cells; Th17 cells