Opposite roles of STAT and PPARgamma in the induction of p21WAF1 expression by IL-13 in human peripheral blood monocytes.
The cyclin kinase inhibitor p21WAF1 is expressed in most, if not all, differentiated cells in the human body and represents an important regulator of cell cycle control and terminal differentiation in the monocyte/macrophage lineage. It has been reported in macrophage cell lines that p21WAF1 expression is sensitive to numerous molecules including cytokines, but nothing was known about p21WAF1 regulation in human peripheral blood monocytes in response to Th2 cytokines. We report here, that IL-13 increases p21WAF1 expression in human blood monocytes. This induction is a transcription-dependent event, leading to an increase in mRNA content. We show that the signalling pathway for IL-13-induced p21WAF1 expression may involve the IL-4R alpha and the IL-13R alpha1 chains, and the tyrosine and JAK2 kinases. Also, p21WAF1 plasmid-based gene activation only requires a minimal p21WAF1 promoter, containing a putative PPRE. Since IL-13 signalisation involves PPARgamma, we tested PPARgamma involvement in p21WAF1 gene activation by using metabolic inhibitors of arachidonic acid metabolism, or by restoring PPARgamma expression in a defective cell line. We found that inhibition of PPARgamma increases IL-13-induced p21WAF1 gene expression in these models. These data argue that IL-13 upregulates p21WAF1 expression in monocytes via JAK/STAT pathway, and that the activation of PPARgamma by this cytokine can counteract this induction.
Dubourdeau
Marc
M
Macrophages, médiateurs de l'inflammation et interactions cellulaires UPRES EA 2405 - INSERM IFR 31, CHU Rangueil, Toulouse, France.
Chêne
Gérald
G
Coste
Agnès
A
Bernad
José
J
Lepert
Jean-Claude
JC
Orfila
Claudine
C
Pipy
Bernard
B
Rousseau
Denis
D
D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000378:metabolism*; D013379:Substrate Specificity; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation
C477819:15-deoxyprostaglandin J2; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018793:Interleukin-13; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D015230:Prostaglandin D2