PGC-1α regulates the expression and activity of IRF-1.

Interferon regulatory transcription factor 1 (IRF-1) regulates downstream signals of tumor necrosis factor α (TNF-α). The activity of IRF-1 is mediated by Jak/Stat signaling pathway. In this study, we found that PPAR γ coactivator-1α (PGC-1α) is able to suppress the induction of IRF-1. Treatment with TNF-α in MC3T3 cells leads to a sustainable increase in the expression of IRF-1 and its target gene cyclooxygenase 2 (COX-2). In contrast, TNF-α treatment led to a sustainable reduction in expression of PGC-1α. Interestingly, we found that overexpression of PGC-1α attenuated the induction of IRF-1 and COX-2. However, silence of PGC-1α exacerbated the induction of IRF-1 and COX-2. Importantly, we found that the effect of PGC-1α on repressing IRF-1 expression and activity is facilitated by the reduction in phosphorylation of STAT1 at position 727 (S727P), an essential transcriptional activator of IRF-1. Finally, we found that calyculin A, a pharmacological inhibitor of protein phosphatase 2A (PP2A) and PP1 abolishes the repression of STAT1 phosphorylation mediated by PGC-1α, suggesting a new mechanism of PGC-1α in regulating STAT1/IRF-1 pathway.