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

Authors
 Soo-jin Ann  ;  Ji Hyung Chung  ;  Byung Hee Park  ;  Soo Hyuk Kim  ;  Jiyoung Jang  ;  Sungha Park  ;  Seok-Min Kang  ;  Sang-Hak Lee 
Citation
 ATHEROSCLEROSIS, Vol.240(2) : 389-397, 2015 
Journal Title
 ATHEROSCLEROSIS 
ISSN
 0021-9150 
Issue Date
2015
MeSH
Animals ; Anti-Inflammatory Agents/pharmacology* ; Cell Line ; Culture Media, Conditioned/metabolism ; Dose-Response Relationship, Drug ; Fenofibrate/pharmacology* ; Gemfibrozil/pharmacology* ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/prevention & control* ; Inflammation Mediators/metabolism ; Lipopolysaccharides/pharmacology ; Macrophage Activation/drug effects* ; Macrophages/drug effects* ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Oxazoles/pharmacology ; PPAR alpha/agonists* ; PPAR alpha/antagonists & inhibitors ; PPAR alpha/metabolism ; RNA Interference ; Signal Transduction/drug effects ; Toll-Like Receptor 4/metabolism ; Transfection ; Tyrosine/analogs & derivatives ; Tyrosine/pharmacology ; Up-Regulation ; beta-Defensins/genetics ; beta-Defensins/metabolism*
Keywords
Atherosclerosis ; Beta-defensins ; Fenofibrate ; Gemfibrozil ; Toll-like receptor 4
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0021915015002233
DOI
10.1016/j.atherosclerosis.2015.04.005
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kang, Seok Min(강석민) ORCID logo https://orcid.org/0000-0001-9856-9227
Kim, Soo Hyuk(김수혁)
Park, Byung Hee(박병희)
Park, Sung Ha(박성하) ORCID logo https://orcid.org/0000-0001-5362-478X
Ann, Soo Jin(안수진)
Lee, Sang Hak(이상학) ORCID logo https://orcid.org/0000-0002-4535-3745
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139968
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