Nuclear Receptors as Targets for Drug Development: Crosstalk Between Peroxisome Proliferator-Activated Receptor γ and Cytokines in Bone Marrow-Derived Mesenchymal Stem Cells

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear receptor and regulates adipogenesis and fat metabolism. PPARγ is activated by fatty acid derivatives and some synthetic compounds such as the thiazolidinediones. In addition, certain cytokines were known to affect the transactivation function of PPARγ. However, the molecular mechanism of the functional interaction between PPARγ and cytokine signaling remains unclear. We found that combined treatment of PPARγ and cytokines (IL-1 or TNF-α) inhibited adipogenesis and induced osteoblastgenesis in bone marrow-derived mesenchymal stem cells. Furthermore, we showed that the ligand dependent transactivation function of PPARγ was suppressed by IL-1 and TNF-α. This suppression was mediated through NF-κB activated by the TAK1/TAB1-NIK cascade, a downstream cascade triggered with IL-1 or TNF-α signaling. Thus, we have identified a molecular mechanism of functional cross-talk between PPARγ and cytokine signaling that may provide a theoretical basis for development of novel therapeutical strategies and design of novel compounds for treatment of obesity, diabetes, and some other chronic diseases. Keywords:: nuclear receptor, adipogenesis, cytokine, mesenchymal stem cell, transcription