Regulation of TAK1/TAB1-Mediated IL-1β Signaling by Cytoplasmic PPARβ/δ

The peroxisome proliferator-activated receptor subtypes PPAR alpha, PPAR beta/delta, PPAR gamma are members of the steroid hormone receptor superfamily with well-established functions in transcriptional regulation. Here, we describe an unexpected cytoplasmic function of PPAR beta/delta. Silencing of PPAR beta/delta expression interferes with the expression of a large subset of interleukin-1 beta (IL-1 beta)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1 beta-induced phosphorylation of TAK1 and its downstream effectors, including the NF kappa B alpha inhibitor I kappa B alpha (NFKBIA) and the NF kappa B alpha subunit p65 (RELA). PPAR beta/delta enhances the interaction between TAK1 and the small heat-shock protein HSP27, a known positive modulator of TAK1-mediated IL-1 beta signaling. Consistent with these findings, PPAR beta/delta physically interacts with both the endogenous cytoplasmic TAK1/TAB1 complex and HSP27, and PPAR beta/delta overexpression increases the TAK1-induced transcriptional activity of NF kappa B. These observations suggest that PPAR beta/delta plays a role in the assembly of a cytoplasmic multi-protein complex containing TAK1, TAB1, HSP27 and PPAR beta/delta, and thereby participates in the NF kappa B response to IL-1 beta.