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Cited by 140Peroxisome Proliferator-Activated ReceptorsImmune Response and InflammationNF-κB Signaling Pathways

Toll‐like receptor 4 mediates cross‐talk between peroxisome proliferator‐activated receptor γ and nuclear factor‐κB in macrophages

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Necela, Brian M., Su, Weidong, Thompson, E. Aubrey·2008·Immunology
DOI 10.1111/j.1365-2567.2008.02849.xPMC PMC2669138
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Abstract

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

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Authors
Necela, B. M., Su, W., & Thompson, E. A.
Affiliations
Mayo Clinic (US)
Corresponding author
  • Necela, Brian M.
  • Thompson, E. Aubrey
ORCID
Venue
Immunology
Publisher
Wiley
Published
2008-10-08
Volume
125
Issue
3
Pages
344-358
ISSN
  • 0019-2805 (ISSN-L)
  • 1365-2567
DOI
10.1111/j.1365-2567.2008.02849.x
PMC
PMC2669138
OpenAlex
W2054531769
Cited by
140
References
8
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FWCI
4.12
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
TLR4, PPARγ, NF-κB, macrophages, lipopolysaccharide, inflammation, NEMO, IκB, anti-inflammatory signaling, proinflammatory state, TLR4 signaling
MeSH terms
Animals, Cell Line, Transformed, Cells, Cultured, Gene Expression Regulation, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Down-Regulation, NF-kappa B, Macrophages, Peritoneal, Mice, Knockout, Genomics, PPAR gamma, Toll-Like Receptors, Toll-Like Receptor 4, Mice

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