title: 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.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Whajung
authors.initials: W
authors.lastname: Cho
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
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: D051546:Cyclooxygenase 2 / Q000378:metabolism*; D020566:Dendritic Cells, Follicular / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000096:biosynthesis*; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018793:Interleukin-13; D007378:Interleukins; D011453:Prostaglandins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D020928:Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases