Toll-like receptor 4 mediates cross-talk between peroxisome proliferator-activated receptor gamma and nuclear factor-kappaB in macrophages.

摘要

The peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in macrophages and plays an important role in suppressing the inflammatory response. Lipopolysaccharides (LPS), which activate Toll-like receptor 4 (TLR4), reduced PPARgamma expression and function in peritoneal macrophages and macrophage cell lines. Moreover, pretreatment with the synthetic PPARgamma ligand, rosiglitazone did not prevent LPS-mediated downregulation of PPARgamma. Inhibition of PPARgamma expression was not blocked by cycloheximide, indicating that de novo protein synthesis is not required for LPS-mediated suppression of PPARgamma. Destabilization of PPARgamma messenger RNA (mRNA) was not observed in LPS-stimulated macrophages, suggesting that LPS regulates the synthesis of PPARgamma mRNA. LPS had no effect on PPARgamma expression in macrophages from TLR4 knockout mice, whereas LPS inhibited PPARgamma expression in cells that had been reconstituted to express functional TLR4. Targeting the TLR4 pathway with inhibitors of MEK1/2, p38, JNK and AP-1 had no effect on PPARgamma downregulation by LPS. However, inhibitors that target NEMO, IkappaB and NF-kappaB abolished LPS-mediated downregulation of PPARgamma in LPS-stimulated macrophages. Our data indicate that activation of TLR4 inhibits PPARgamma mRNA synthesis by an NF-kappaB-dependent mechanism. Low-density genomic profiling of macrophage-specific PPARgamma knockout cells indicated that PPARgamma suppresses inflammation under basal conditions, and that loss of PPARgamma expression is sufficient to induce a proinflammatory state. Our data reveal a regulatory feedback loop in which PPARgamma represses NF-kappaB-mediated inflammatory signalling in unstimulated macrophages; however, upon activation of TLR4, NF-kappaB drives down PPARgamma expression and thereby obviates any potential anti-inflammatory effects of PPARgamma in LPS-stimulated macrophages.