PPARα agonists inhibit inflammatory activation of macrophages through upregulation of β-defensin 1

Soo jin Ann, Ji Hyung Chung, Byung Hee Park, Soo Hyuk Kim, Jiyoung Jang, Sungha Park, Seok Min Kang, Sang Hak Lee

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists on cardiovascular outcome have been controversial. Although these agents primarily affect lipoprotein metabolism, their pleiotropic anti-inflammatory effect is one of the potential anti-atherosclerotic mechanisms. This study aimed to evaluate the effect of fenofibrate and gemfibrozil on inflammation in macrophages and reveal pathways these agents may affect. Methods and results: The two PPARα agonists inhibited secretion of CXCL2, TNF-α, IL-6, activation of p65 of NF-κB, ERK, and TLR4 expression. These changes occurred simultaneously with upregulation and secretion of β-defensin 1, an inflammation-modulating peptide. To demonstrate the role of β-defensin 1, it was knocked-down by target-specific siRNA. The effects of PPARα agonists on TLR4 expression and chemokine secretion were obviously abrogated with this treatment. In experiments investigating whether β-defensin 1 acts extracellularly, inflammatory chemokines decreased significantly after the addition of recombinant β-defensin 1 or conditioned media to cells. In experiments designed to clarify if the effects of the two agents are PPARα-dependent, induction of mRNA and secretion β-defensin 1 and inhibition of chemokine release were clearly reduced with GW6471, a PPARα blocker. Conclusions: Our results reveal the pathways by which fenofibrate and gemfibrozil inhibit LPS-induced inflammatory activation of macrophages. This study elucidated a novel anti-inflammatory mechanism that acts through PPARα, β-defensin 1, and TLR4 pathways.

Original languageEnglish
Pages (from-to)389-397
Number of pages9
JournalAtherosclerosis
Volume240
Issue number2
DOIs
Publication statusPublished - 2015 Jun 1

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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