ABSTRACT
The peroxisome proliferator-activated receptor subtypes PPARα, PPARß/δ, PPARγ are members of the steroid hormone receptor superfamily with well-established functions in transcriptional regulation. Here, we describe an unexpected cytoplasmic function of PPARß/δ. Silencing of PPARß/δ expression interferes with the expression of a large subset of interleukin-1ß (IL-1ß)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1ß-induced phosphorylation of TAK1 and its downstream effectors, including the NFκBα inhibitor IκBα (NFKBIA) and the NFκBα subunit p65 (RELA). PPARß/δ enhances the interaction between TAK1 and the small heat-shock protein HSP27, a known positive modulator of TAK1-mediated IL-1ß signaling. Consistent with these findings, PPARß/δ physically interacts with both the endogenous cytoplasmic TAK1/TAB1 complex and HSP27, and PPARß/δ overexpression increases the TAK1-induced transcriptional activity of NFκB. These observations suggest that PPARß/δ plays a role in the assembly of a cytoplasmic multi-protein complex containing TAK1, TAB1, HSP27 and PPARß/δ, and thereby participates in the NFκB response to IL-1ß.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Interleukin-1beta/metabolism , MAP Kinase Kinase Kinases/metabolism , PPAR delta/metabolism , PPAR-beta/metabolism , Signal Transduction , Cytoplasm/metabolism , Gene Expression Profiling , Gene Expression Regulation , HSP27 Heat-Shock Proteins/metabolism , HeLa Cells , Humans , Interleukin-1beta/pharmacology , MAP Kinase Kinase Kinases/chemistry , Protein Binding , Protein Interaction Domains and Motifs , Transcription Factor RelA/metabolism , Transcription, Genetic/drug effectsABSTRACT
Previous work has provided strong evidence for a role of peroxisome proliferator-activated receptor ß/δ (PPARß/δ) and transforming growth factor-ß (TGFß) in inflammation and tumor stroma function, raising the possibility that both signaling pathways are interconnected. We have addressed this hypothesis by microarray analyses of human diploid fibroblasts induced to myofibroblastic differentiation, which revealed a substantial, mostly reverse crosstalk of both pathways and identified distinct classes of genes. A major class encompasses classical PPAR target genes, including ANGPTL4, CPT1A, ADRP and PDK4. These genes are repressed by TGFß, which is counteracted by PPARß/δ activation. This is mediated, at least in part, by the TGFß-induced recruitment of the corepressor SMRT to PPAR response elements, and its release by PPARß/δ ligands, indicating that TGFß and PPARß/δ signals are integrated by chromatin-associated complexes. A second class represents TGFß-induced genes that are downregulated by PPARß/δ agonists, exemplified by CD274 and IL6, which is consistent with the anti-inflammatory properties of PPARß/δ ligands. Finally, cooperative regulation by both ligands was observed for a minor group of genes, including several regulators of cell proliferation. These observations indicate that PPARß/δ is able to influence the expression of distinct sets of both TGFß-repressed and TGFß-activated genes in both directions.
