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European Cytokine Network

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Opposite roles of STAT and PPARγ in the induction of p21 WAF1 expression by IL-13 in human peripheral blood monocytes Volume 19, numéro 4, December 2008

Auteurs
Macrophages, médiateurs de l’inflammation et interactions cellulaires UPRES EA 2405 - INSERM IFR 31, CHU Rangueil, Toulouse, France, Ambiotis, Incubateur Midi-Pyrénées, 29 rue Jeanne Marvig, 31400 Toulouse, France, CEA, DSV, iRTSV, Laboratoire de biochimie et biophysique des systèmes intégrés, 38054 Grenoble, and Université Joseph Fourier, Grenoble, France

The cyclin kinase inhibitor p21 WAF1 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 p21 WAF1 expression is sensitive to numerous molecules including cytokines, but nothing was known about p21 WAF1 regulation in human peripheral blood monocytes in response to Th2 cytokines. We report here, that IL-13 increases p21 WAF1 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 p21 WAF1 expression may involve the IL-4R alpha and the IL-13R alpha1 chains, and the tyrosine and JAK2 kinases. Also, p21 WAF1 plasmid-based gene activation only requires a minimal p21 WAF1 promoter, containing a putative PPRE. Since IL-13 signalisation involves PPARγ, we tested PPARγ involvement in p21 WAF1 gene activation by using metabolic inhibitors of arachidonic acid metabolism, or by restoring PPARγ expression in a defective cell line. We found that inhibition of PPARγ increases IL-13-induced p21 WAF1 gene expression in these models. These data argue that IL-13 upregulates p21 WAF1 expression in monocytes via JAK/STAT pathway, and that the activation of PPARγ by this cytokine can counteract this induction.