title: STAT6 and JAK1 are essential for IL-4-mediated suppression of prostaglandin production in human follicular dendritic cells: opposing roles of phosphorylated and unphosphorylated STAT6.
abstract: Prostaglandins (PGs) are emerging as important immune mediators. Since our first report on the expression of prostacyclin synthase in the germinal centers, we have investigated production mechanisms and biological functions of PG using human follicular dendritic cell (FDC)-like cells. In the previous report, we observed that TGF-β enhances PG production, and IL-4 prevents this upregulation. To elucidate the inhibitory mechanism of IL-4, its effects on the key enzyme leading to PG production were analyzed in this study. IL-4 but not IL-10 inhibited TGF-β-induced COX-2 expression at both mRNA and protein levels. Next the early signaling molecules of IL-4 were identified by siRNA technology. IL-4 induced tyrosine phosphorylation of STAT1, 3, and 6, but only JAK1-STAT6 pathway was responsible for the prevention of COX-2 augmentation and PG production. Phosphorylated STAT6 accumulated in the nucleus rapidly upon IL-4 addition, and the complete inhibition of COX-2 upregulation required 24 h of pretreatment with IL-4, implying that newly transcribed molecules mediate the inhibitory signals downstream of STAT6. Interestingly, unphosphorylated STAT6 proteins were constitutively expressed in the nucleus, and depletion of STAT6 impaired background level expression of COX-2 and PGs. Our results highlight the crucial roles of TGF-β and IL-4 in the regulation of PG production, which lead us to suggest that T cells play an important role in FDC production of PGs.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Kangwon National University, Chuncheon, Gangwon, Republic of Korea.
authors.forename: Whajung
authors.initials: W
authors.lastname: Cho
authors.forename: Doo-Il
authors.initials: DI
authors.lastname: Jeoung
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
mesh_terms: D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D020566:Dendritic Cells, Follicular / Q000378:metabolism*; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D011453:Prostaglandins / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D011453:Prostaglandins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1