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

Background: Effects of peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 PPAR alpha agonists inhibited secretion of CXCL2, TNF-alpha, IL-6, activation of p65 of NF-kappa B, ERK, and TLR4 expression. These changes occurred simultaneously with upregulation and secretion of beta-defensin 1, an inflammation-modulating peptide. To demonstrate the role of beta-defensin 1, it was knocked-down by target-specific siRNA. The effects of PPAR alpha agonists on TLR4 expression and chemokine secretion were obviously abrogated with this treatment. In experiments investigating whether beta-defensin 1 acts extracellularly, inflammatory chemokines decreased significantly after the addition of recombinant beta-defensin 1 or conditioned media to cells. In experiments designed to clarify if the effects of the two agents are PPAR alpha-dependent, induction of mRNA and secretion beta-defensin 1 and inhibition of chemokine release were clearly reduced with GW6471, a PPAR alpha 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 PPAR alpha, beta-defensin 1, and TLR4 pathways. (C) 2015 Elsevier Ireland Ltd. All rights reserved.