IL-4 and IL-13 suppress prostaglandins production in human follicular dendritic cells by repressing COX-2 and mPGES-1 expression through JAK1 and STAT6

초록

Originally discovered as a B cell growth and differentiation factor, IL-4 displays a variety of functions in many different cell types. Germinal center T cells are abundant producers of IL-4. In a recent report, we demonstrated that IL-4 inhibits prostaglandins (PGs) production in follicular dendritic cell (FDC)-like cells, HK. To understand the inhibitory mechanisms of IL-4, its effects on the biosynthesis of enzymes in charge of PG production were assessed in this study. Although IL-4 did not affect COX-1 expression, it specifically inhibited LPS-induced COX-2 biosynthesis at mRNA and protein levels. Protein expression of mPGES-1, a downstream enzyme of COX-2, was also markedly diminished by IL-4 but not by IL-10, maximizing the inhibitory activity. Next, we attempted to identify the early signaling molecules that led to this inhibition of COX-2 expression. Although IL-4 induced tyrosine phosphorylation of JAK1 and TYK2, RNA interference experiments revealed that only JAK1 was responsible for the IL-4-stimulated STAT6 phosphorylation. Knocking down JAK1 and STAT6 ablated the inhibitory effect of IL-4 on COX-2 expression and significantly reduced production of PGE(2) and prostacyclin. Similar results were obtained with IL-13. Pharmacologic inhibitors of ERK and p38 mitogen-activated protein kinases inhibited the COX-2 upregulation. However, IL-4 did not affect LPS-induced phosphorylation of ERK and p38. These results stress the essential roles of JAK1 and STAT6 in the early signaling pathway of IL-4 and IL-13 leading to suppression of COX-2 expression and repression of PG production by HK cells. Our results suggest that T cells via IL-4 play a regulatory role in PG generation in FDC. IL-4 therapeutics may be applied to immune disorders where normal and ectopic expression of germinal center reactions needs to be regulated. (C) 2011 Elsevier Ltd. All rights reserved.

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