Soo-Jin Ann1, Ji Hyung Chung2, Byung Hee Park1, Soo Hyuk Kim1, Jiyoung Jang3, Sungha Park4, Seok-Min Kang4, Sang-Hak Lee5. 1. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. 2. Department of Applied Bioscience, School of Biomedical Science, Cha University, Seongnam, Republic of Korea. 3. Department of Microbiology, Yonsei University College of Medicine, Seoul, Republic of Korea. 4. 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. 5. 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.
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.
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.