Immunity
Volume 33, Issue 5, 24 November 2010, Pages 699-712
Journal home page for Immunity

Article
STAT6 Transcription Factor Is a Facilitator of the Nuclear Receptor PPARγ-Regulated Gene Expression in Macrophages and Dendritic Cells

https://doi.org/10.1016/j.immuni.2010.11.009Get rights and content
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Summary

Peroxisome proliferator-activated receptor γ (PPARγ) is a lipid-activated transcription factor regulating lipid metabolism and inflammatory response in macrophages and dendritic cells (DCs). These immune cells exposed to distinct inflammatory milieu show cell type specification as a result of altered gene expression. We demonstrate here a mechanism how inflammatory molecules modulate PPARγ signaling in distinct subsets of cells. Proinflammatory molecules inhibited whereas interleukin-4 (IL-4) stimulated PPARγ activity in macrophages and DCs. Furthermore, IL-4 signaling augmented PPARγ activity through an interaction between PPARγ and signal transducer and activators of transcription 6 (STAT6) on promoters of PPARγ target genes, including FABP4. Thus, STAT6 acts as a facilitating factor for PPARγ by promoting DNA binding and consequently increasing the number of regulated genes and the magnitude of responses. This interaction, underpinning cell type-specific responses, represents a unique way of controlling nuclear receptor signaling by inflammatory molecules in immune cells.

Highlights

► Proinflammatory cytokines inhibit and IL-4 stimulates PPARγ activity in macrophages ► IL-4 acts as an upstream regulator of PPARγ signaling via STAT6 ► STAT6 and PPARγ bind to target gene promoters together and physically interact ► STAT6 promotes PPARγ binding and facilitates its transcriptional activity

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Present address: Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Richard Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA