Abstract
The peroxisome proliferator-activated receptor subtypes PPARα, PPARβ/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 PPARβ/δ. Silencing of PPARβ/δ expression interferes with the expression of a large subset of interleukin-1β (IL-1β)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1β-induced phosphorylation of TAK1 and its downstream effectors, including the NFκBα inhibitor IκBα (NFKBIA) and the NFκBα subunit p65 (RELA). PPARβ/δ enhances the interaction between TAK1 and the small heat-shock protein HSP27, a known positive modulator of TAK1-mediated IL-1β signaling. Consistent with these findings, PPARβ/δ physically interacts with both the endogenous cytoplasmic TAK1/TAB1 complex and HSP27, and PPARβ/δ overexpression increases the TAK1-induced transcriptional activity of NFκB. These observations suggest that PPARβ/δ plays a role in the assembly of a cytoplasmic multi-protein complex containing TAK1, TAB1, HSP27 and PPARβ/δ, and thereby participates in the NFκB response to IL-1β.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-inducible transcription factors [1,2]
PPARb/d inhibited p65-induced NFkB activation (Figure 5F), which is consistent with the proposed inhibitory effect of PPARb/d ligands on NFkB activity
No significant effect was seen on basal level of NFkB activity in all three experiments, suggesting that the stimulatory PPARb/d effect is dependent on IL-1b induced TAK1/TAB1 signaling
Summary
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-inducible transcription factors [1,2]. Consistent with their regulation by fatty acids and eicosanoid metabolites, PPARs function as modulators of lipid metabolism and inflammatory responses. There is a large body of evidence implicating PPARb/d in inflammation-associated processes This evidence is based on the observation that the expression of PPARb/d or its ligands is regulated by different cytokines (such as TNFa, TGFb or IL-4) or small molecular modulators of inflammation, such as leukotrienes and hydroxyeicosatetraenoic acid [4,5,6,7,8]. Multiple molecular mechanisms underlying these observations have been identified, which places PPARb/d into a complex regulatory network
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