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, seokmin kang, Sang Hak Lee

Research output: Contribution to journalArticle

8 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

Fingerprint

Defensins
PPAR alpha
Macrophage Activation
Up-Regulation
Chemokines
Gemfibrozil
Fenofibrate
Anti-Inflammatory Agents
alpha-Defensins
Inflammation
Conditioned Culture Medium
Small Interfering RNA
Lipoproteins
Interleukin-6
Macrophages
Messenger RNA
Peptides

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Ann, Soo jin ; Chung, Ji Hyung ; Park, Byung Hee ; Kim, Soo Hyuk ; Jang, Jiyoung ; Park, Sungha ; kang, seokmin ; Lee, Sang Hak. / PPARα agonists inhibit inflammatory activation of macrophages through upregulation of β-defensin 1. In: Atherosclerosis. 2015 ; Vol. 240, No. 2. pp. 389-397.
@article{0a28265b461f4cde9a1bb306624842fb,
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. 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.",
author = "Ann, {Soo jin} and Chung, {Ji Hyung} and Park, {Byung Hee} and Kim, {Soo Hyuk} and Jiyoung Jang and Sungha Park and seokmin kang and Lee, {Sang Hak}",
year = "2015",
month = "6",
day = "1",
doi = "10.1016/j.atherosclerosis.2015.04.005",
language = "English",
volume = "240",
pages = "389--397",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier Ireland Ltd",
number = "2",

}

PPARα agonists inhibit inflammatory activation of macrophages through upregulation of β-defensin 1. / Ann, Soo jin; Chung, Ji Hyung; Park, Byung Hee; Kim, Soo Hyuk; Jang, Jiyoung; Park, Sungha; kang, seokmin; Lee, Sang Hak.

In: Atherosclerosis, Vol. 240, No. 2, 01.06.2015, p. 389-397.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PPARα agonists inhibit inflammatory activation of macrophages through upregulation of β-defensin 1

AU - Ann, Soo jin

AU - Chung, Ji Hyung

AU - Park, Byung Hee

AU - Kim, Soo Hyuk

AU - Jang, Jiyoung

AU - Park, Sungha

AU - kang, seokmin

AU - Lee, Sang Hak

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84927591067&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927591067&partnerID=8YFLogxK

U2 - 10.1016/j.atherosclerosis.2015.04.005

DO - 10.1016/j.atherosclerosis.2015.04.005

M3 - Article

C2 - 25881202

AN - SCOPUS:84927591067

VL - 240

SP - 389

EP - 397

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

IS - 2

ER -