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

作者：Necela Brian M^*; Su Weidong; Thompson E Aubrey

来源：Immunology, 2008, 125(3): 344-358.

DOI：10.1111/j.1365-2567.2008.02849.x

• inflammatory
• macrophage
• nuclear factor-kappa B
• peroxisome proliferator-activated receptor gamma
• Toll-like receptor

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

• 出版日期2008-11