Highlights
- •PPARα agonists inhibited inflammation with β-defensin 1 upregulation.
- •This effect was abrogated with silencing of β-defensin 1.
- •Inflammation decreased with recombinant β-defensin 1 or conditioned media.
- •Induction of β-defensin 1 was PPARα-dependent.
- •A novel pathway by which PPARα agonists inhibit inflammation was shown.
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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.N. Engl. J. Med. 1999; 341: 410-418
- Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.Lancet. 2005; 366: 1849-1861
- Effects of combination lipid therapy in type 2 diabetes mellitus.N. Engl. J. Med. 2010; 362: 1563-1574
- PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation.Biochim. Biophys. Acta. 2011; 1812: 1007-1022
- Peroxisome proliferator-activated receptor alpha negatively regulated the vascular inflammatory gene response by negative cross-talk with transcription factor NF-κB and AP-1.J. Biol. Chem. 1999; 274: 32681-32687
- Defensins. Natural peptide antibiotics of human neutrophils.J. Clin. Invest. 1985; 76: 1427-1435
- Defensins: antimicrobial peptides of innate immunity.Nat. Rev. Immunol. 2003; 3: 710-720
- Induction of porcine host defense peptide gene expression by short-chain fatty acids and their analogs.PLoS One. 2013; 8: e72922
- PPARs at the crossroads of lipid signaling and inflammation.Trends Endocrinol. Metab. 2012; 23: 351-363
- Peroxisome proliferator-activated receptor gamma negatively regulates IFN- production in toll-like receptor (TLR) 3- and TLR4-stimulated macrophages by preventing interferon regulatory factor 3 binding to the IFN-beta promoter.J. Biol. Chem. 2011; 286: 5519-5528
- PPARγ agonists inhibit Toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-κB pathways.Blood. 2005; 106: 3888-3894
- Peroxisome proliferator-activated receptor-α modulates insulin gene transcription factors and inflammation in adipose tissues in mice.Mol. Cell Biochem. 2009; 323: 101-111
- HMGB1 is involved in the protective effect of the PPAR agonist fenofibrate against cardiac hypertrophy.PPAR Res. 2014; 2014: 541394
- The novel beta-defensin DEFB123 prevents lipopolysaccharide-mediated effects in vitro and in vivo.FASEB J. 2006; 20: 1701-1702
- Human–defensin3 affects the activity of pro-inflammatory pathways associated with MyD88 and TRIF.Eur. J. Immunol. 2011; : 413291-413300
- Palmitate promotes the paracrine effects of macrophages on vascular smooth muscle cells: the role of bone morphogenetic proteins.PLoS One. 2012; 7: e29100
Article info
Publication history
Published online: April 07, 2015
Accepted:
April 2,
2015
Received in revised form:
March 10,
2015
Received:
December 10,
2014
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
