A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity
Stat6 tanscription factor is a facilitator of the nuclear receptor PPARg-regulated gene expression in macrophages and dendritic cells
Attila Szanto, et al. (2010) Immunity. 33, 699-712
Speaker: Miao-Hsi Hsieh (謝妙禧) Time: 13:10~14:00, Apr. 20, 2011
Commentator: Pei-Jane Tsai (蔡佩珍 老師) Place: Room 601
Abstract:
Peroxisome proliferator-activated receptor gamma (PPARg) is a ligand-activated transcription factor and regulating adipogenesis, lipid metabolism and inflammation. When PPARg�nactived, it form heterodimer with retinoid X receptor (RXR) that binds to PPAR response elements (PPREs)in the promotor region of target genes and activates transcription. Huang at (1999) found that Th2 cytokine IL-4 was a strong inducer of PPARg expressionin in macrophages. However, the transcriptional underpinnings of IL-4-PPARg cross-talk in alternatively activated macrophages have remained poorly understood. The author aimed to understand the impact of extracellular signals on PPARg activity in macrophages. First, they found the induction of PPARg by IL-4 and IL-4 combined with PPARg agonist rosiglitazone (RSG) in human and mouse monocyte-derived macrophages. Second, they wanted to understand the relationship between PPARg-IL-4 in macrophage, and created a macrophage-specific PPARg-deficient mice carrying null allels Ppargfl/-. They found the very little influence between bone marrow-derived macrophage from Pparg+/- andPpargfl/- LysCre mice treated with IL-4 and RSG. The authors suggested that PPARg was largely dispensable for IL-4-regulate gene expression in macrophage, but downstream effactor of IL-4 may impact PPARg expression. They used many inhibitors to screen this expression signal, and finally found that JAK3 and JAK3 downstream substrate, STAT6, were required for PPARg gene expression. Third, they found STAT6 facilitate PPARg signaling at transcriptional level by interaction with PPARg and bound to the PPREs. Overall the findings bring the additional mechanism between IL-4 and PPARg in the macrophage, and also prove the exact direction in this signal pathway.
References:
- Jannet T. Huang, et al. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. (1999) Nature 400,378-82.
- Claudo J. Villanueva, et al. Licensing PPARg to work in macrophage. (2010) Immunity. 33,647-649