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

Peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma signaling in distinct subsets of cells. Proinflammatory molecules inhibited whereas interleukin-4 (IL-4) stimulated PPAR gamma activity in macrophages and DCs. Furthermore, IL-4 signaling augmented PPAR gamma activity through an interaction between PPAR gamma and signal transducer and activators of transcription 6 (STAT6) on promoters of PPAR gamma target genes, including FABP4. Thus, STAT6 acts as a facilitating factor for PPAR gamma 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.