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

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• 作者：Whajung Cho^a ; Doo-Il Jeoung^b ; Young-Myeong Kim^c ; Jongseon Choe^a ; ^{jchoe@kangwon.ac.kr}
• 关键词：FDC ; follicular dendritic cell ; GC ; germinal center ; JAK ; Janus kinase ; STAT ; signal transducer and activator of transcription ; U-STAT6 ; unphosphorylated STAT6 ; P-STAT6 ; phosphorylated STAT6
• 刊名：International Immunopharmacology
• 出版年：2012
• 期刊代码：123_15675769
• 类别：med
• 出版时间：April, 2012
• 卷：12
• 期：4
• 页码：635-642
• 文件大小：1167 K

摘要

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-尾 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-尾-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-尾 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.