PPARγ agonist rosiglitazone ameliorates LPS-induced inflammation in vascular smooth muscle cells via the TLR4/TRIF/IRF3/IP-10 signaling pathway.

Abstract

The activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) can induce inflammation that are one of key etiological conditions for the development of many chronic inflammatory diseases including atherosclerosis and diabetes. Peroxisome proliferator-activated receptor γ (PPARγ) agonists play a crucial role in improving glucose and lipid homeostasis in the development of cardiovascular diseases. Evidence is growing that benefits of PPARγ agonists may also be derived from the anti-inflammatory and anti-atherosclerotic properties of these agents. However, the role of rosiglitazone in regulating LPS-induced vascular inflammation has yet to be fully elucidated. The current study demonstrated that rosiglitazone exerted a potent anti-inflammatory action via decreasing interleukin-18 (IL-18), tissue inhibitor of metalloproteinase-1 (TIMP-1), TLR4 and increasing PPARγ in LPS-induced VSMCs. Furthermore, treatment of VSMCs with the TLR4 blocker or TLR4 small-interfering RNA presented that the regulatory effects of rosiglitazone on LPS-mediated inflammation in VSMCs were dependent on TLR4. Interestingly, the results indicated that beneficial effects of rosiglitazone on LPS-induced inflammation in VSMCs were mediated via interference of TLR4 and its downstream signaling components including Toll-interleukin-1 (IL-1) receptor domain-containing adaptor inducing interferon-β (TRIF), interferon regulatory factor 3 (IRF3) and interferon-gamma inducible protein 10 (IP-10). In summary, PPARγ agonist rosiglitazone exerts anti-inflammatory property by antagonizing LPS-mediated inflammation in VSMCs. More importantly, the regulation of the TRIF-dependent TLR4 signaling pathway (TLR4/TRIF/ IRF3/IP-10) provides new insight to understand the mode of action of rosiglitazone for its anti-inflammatory effects.

• Authors: Yuanyuan Ji, Juntian Liu, Zhidong Wang, Zongfang Li
• Journal: Cytokine (Cytokine) Vol. 55 Issue 3 Pg. 409-19 (Sep 2011) ISSN: 1096-0023 [Electronic] England
• PMID: 21700474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Anti-Inflammatory Agents
• Chemokine CXCL10
• Cxcl10 protein, rat
• Interferon Regulatory Factor-3
• Interleukin-18
• Lipopolysaccharides
• PPAR gamma
• RNA, Small Interfering
• Thiazolidinediones
• Ticam1 protein, rat
• Tissue Inhibitor of Metalloproteinase-1
• Tlr4 protein, rat
• Toll-Like Receptor 4
• Rosiglitazone

Topics

• Adaptor Proteins, Vesicular Transport (metabolism)
• Animals
• Anti-Inflammatory Agents
• Cells, Cultured
• Chemokine CXCL10 (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Inflammation (immunology)
• Interferon Regulatory Factor-3 (metabolism)
• Interleukin-18 (immunology, metabolism)
• Lipopolysaccharides (immunology, pharmacology)
• Male
• Muscle, Smooth, Vascular (drug effects, immunology, metabolism, pathology)
• PPAR gamma (agonists, genetics, metabolism)
• RNA Interference
• RNA, Small Interfering
• Rats
• Rats, Sprague-Dawley
• Rosiglitazone
• Signal Transduction (drug effects, immunology)
• Thiazolidinediones (pharmacology)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Toll-Like Receptor 4 (genetics, metabolism)