title: PPARα agonists inhibit inflammatory activation of macrophages through upregulation of β-defensin 1.
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.
  
  
  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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Ann
authors.affiliation: Department of Applied Bioscience, School of Biomedical Science, Cha University, Seongnam, Republic of Korea.
authors.forename: Ji Hyung
authors.initials: JH
authors.lastname: Chung
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Byung Hee
authors.initials: BH
authors.lastname: Park
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Soo Hyuk
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Jang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; Cardiovascular Research Institute, Yonsei University Health System, Seoul, Republic of Korea.
authors.forename: Sungha
authors.initials: S
authors.lastname: Park
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; Cardiovascular Research Institute, Yonsei University Health System, Seoul, Republic of Korea.
authors.forename: Seok-Min
authors.initials: SM
authors.lastname: Kang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; Cardiovascular Research Institute, Yonsei University Health System, Seoul, Republic of Korea. Electronic address: shl1106@yuhs.ac.
authors.forename: Sang-Hak
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000494:pharmacology*; D015248:Gemfibrozil / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D017077:Culture Media, Conditioned; C120555:Defb1 protein, mouse; C449302:GW 6471; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010080:Oxazoles; D047493:PPAR alpha; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D023083:beta-Defensins; D014443:Tyrosine; D015248:Gemfibrozil; D011345:Fenofibrate
keywords: Atherosclerosis; Beta-defensins; Fenofibrate; Gemfibrozil; Toll-like receptor 4