Elsevier

Immunobiology

Volume 213, Issues 9–10, 6 November 2008, Pages 789-803
Immunobiology

Review
The many faces of PPARγ: Anti-inflammatory by any means?

https://doi.org/10.1016/j.imbio.2008.07.015Get rights and content

Abstract

The peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily, a group of transcription factors that regulate expression of their target genes upon ligand binding. As endogenous ligands, oxidized fatty acids and prostanoids can bind to and activate the receptor. Natural and synthetic PPARγ activators have been studied extensively in many inflammatory settings and in most instances they have been shown to be anti-inflammatory. In this review we give an overview of the different molecular mechanisms how PPARγ and its agonists exert their anti-inflammatory effects both at the cellular level and the level of the organism. The action of PPARγ in acute and chronic inflammatory diseases and disease models will be presented.

Introduction

PPARγ belongs to the nuclear receptor superfamily of transcription factors. These transcription factors function as receptors for various lipid-soluble, small molecules that are most commonly generated as hormones or in the intermediary metabolic pathways. Therefore, nuclear receptors function as metabolic sensors that in turn regulate gene expression programs according to the metabolic state of the cell or organ. Moreover, these receptors by regulating the transcription of many genes involved in other processes, like inflammation and differentiation serve as communicators between metabolic, inflammatory and developmental reactions (Kersten et al., 2000; Kliewer et al., 1999). In the nuclear receptor superfamily there are receptors like the classical steroid hormone receptors (e.g. glucocorticoid receptors) that are localized in the cytosol in an inactive form and upon ligand binding they are translocated into the nucleus where as homodimers they bind to specific response elements of the target genes. Another group of nuclear receptors are located in the nucleus without ligand binding and usually work as heterodimers of the retinoid X receptor (RXR) (Szanto et al., 2004). Members of this group can repress transcription without ligand binding and induce gene expression upon stimulus (Mangelsdorf et al., 1995). Here we are focusing on an RXR partner receptor, PPARγ and its role in regulating inflammatory processes.

PPARγ was originally described in differentiating adipocytes (Tontonoz et al., 1994), later it was identified in other tissues (Kliewer et al., 1994) and a role in macrophages (Nagy et al., 1998; Ricote et al., 1998; Tontonoz et al., 1998) and dendritic cells (DCs) was also discovered (Faveeuw et al., 2000; Gosset et al., 2001; Nencioni et al., 2002; Szatmari et al., 2004; Szeles et al., 2007). It is essential during adipogenesis (Barak et al., 1999; Brun et al., 1996) and required for normal mouse development, especially for placental development and vascularization (Barak et al., 1999; Kubota et al., 1999; Rosen et al., 1999; Tarrade et al., 2001a, Tarrade et al., 2001b). In macrophages PPARγ regulates metabolic processes and inflammation. By coordinating cholesterol uptake and efflux the receptor is a central player in foam cell formation, one of the earliest steps during atherogenesis (Chawla et al., 2001b; Nagy et al., 1998; Tontonoz et al., 1998). As part of these studies several lipid molecules were shown to activate the receptor: components of oxidized low-density lipoprotein, 9-hydroxy octadecadienoic acid (9-HODE) and 13-HODE were described as endogenous ligands for the receptor (Nagy et al., 1998). Another possible natural activator for the PPARγ, the prostanoid 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) was also identified (Forman et al., 1995; Kliewer et al., 1995; Yu et al., 1995). A group of insulin-sensitizer drugs, the thiazolidinedions (TZDs) that are widely used in the treatment of type II diabetes mellitus are synthetic PPARγ agonists (Lehmann et al., 1995). At the time when PPARγ was identified in macrophages its activators were shown to function as potent anti-inflammatory molecules (Ricote et al., 1998). Originally, they were shown to inhibit the response of macrophages to pro-inflammatory stimuli such as lipopolysaccharide (LPS) or interferon-γ (IFNγ). Over the last 10 years natural and synthetic PPARγ ligands have been described to exert multiple anti-inflammatory effects on various levels. Several studies have been performed to analyze the inhibitory role for the receptor and to dissect the molecular mechanisms responsible for the immunosuppressive effects. In this review we provide an overview of the possible mechanisms for the anti-inflammatory function and we also try to summarize the cell types and specific inflammatory reactions where PPARγ seems to exert its anti-inflammatory function.

Section snippets

Suppression of inflammatory reactions in macrophages

PPARγ was shown to be highly expressed in mouse thioglycolate-elicited macrophages and its natural and synthetic ligands inhibited the expression of several molecules involved in the inflammatory process like inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP-9) and scavenger receptor A (Ricote et al., 1998). When similar effects were reported for the PPARγ activators in human monocyte-derived macrophages the receptor attracted attention as a possible therapeutic target in

Experimental autoimmune encephalomyelitis

This is a model for a human disease of the central nervous system, multiple sclerosis, where myelin reactive T cells destroy oligodendrocyte sheets and cause axonal degeneration leading to irreversible disability. The disease is characterized by chronic inflammation and TH1 dominance. PPARγ agonists were shown to attenuate inflammation and reduce symptoms in a mouse model of experimental autoimmune encephalomyelitis while PPARγ-deficient heterozygous mice develop exacerbated encephalomyelitis (

Acknowledgment

L.N. is an International Scholar of HHMI and holds a Wellcome Trust Senior Research Fellowship in Biomedical Sciences. A.Sz. is supported by the Hungarian Academy of Sciences (Bolyai Scholarship) and by grants from Hungarian Science Research Fund (OTKA/61814) and from the University of Debrecen (Mecenatura).

References (136)

  • S. Ghisletti et al.

    Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma

    Mol. Cell

    (2007)
  • S. Goerdt et al.

    Other functions, other genes: alternative activation of antigen-presenting cells

    Immunity

    (1999)
  • H. Hammad et al.

    Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma

    Am. J. Pathol.

    (2004)
  • H. Hasegawa et al.

    Pioglitazone, a peroxisome proliferator-activated receptor gamma activator, ameliorates experimental autoimmune myocarditis by modulating Th1/Th2 balance

    J. Mol. Cell Cardiol.

    (2005)
  • K. Honda et al.

    Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model

    J. Allergy Clin. Immunol.

    (2004)
  • N. Kamei et al.

    Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance

    J. Biol. Chem.

    (2006)
  • S.A. Kliewer et al.

    A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation

    Cell

    (1995)
  • M. Kobayashi et al.

    An inverse relationship between peroxisome proliferator-activated receptor gamma and allergic airway inflammation in an allergen challenge model

    Ann. Allergy Asthma Immunol.

    (2005)
  • N. Kubota et al.

    PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance

    Mol. Cell

    (1999)
  • K.S. Lee et al.

    Peroxisome proliferator activated receptor-gamma modulates reactive oxygen species generation and activation of nuclear factor-kappaB and hypoxia-inducible factor 1alpha in allergic airway disease of mice

    J. Allergy Clin. Immunol.

    (2006)
  • J.M. Lehmann et al.

    An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)

    J. Biol. Chem.

    (1995)
  • M. Lehrke et al.

    CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans

    J. Am. Coll. Cardiol.

    (2007)
  • J.D. Lewis et al.

    An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis

    Am. J. Gastroenterol.

    (2001)
  • A. Maeda et al.

    Pioglitazone attenuates TGF-beta(1)-induction of fibronectin synthesis and its splicing variant in human mesangial cells via activation of peroxisome proliferator-activated receptor (PPAR)gamma

    Cell Biol. Int.

    (2005)
  • D.J. Mangelsdorf et al.

    The nuclear receptor superfamily: the second decade

    Cell

    (1995)
  • L. Nagy et al.

    Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma

    Cell

    (1998)
  • M. Niino et al.

    Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-gamma

    J. Neuroimmunol.

    (2001)
  • E.J. Park et al.

    15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia

    J. Biol. Chem.

    (2003)
  • L. Patel et al.

    Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN

    Curr. Biol.

    (2001)
  • H.P. Raikwar et al.

    PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis

    J. Neuroimmunol.

    (2005)
  • E.D. Rosen et al.

    PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro

    Mol. Cell

    (1999)
  • R. Ruhl et al.

    Inhibition of IgE-production by peroxisome proliferator-activated receptor ligands

    J. Invest. Dermatol.

    (2003)
  • O. Sato et al.

    Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands

    J. Biol. Chem.

    (2002)
  • M. Adachi et al.

    Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease

    Gut

    (2006)
  • D.G. Alleva et al.

    Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-gamma: counter-regulatory activity by IFN-gamma

    J. Leukoc. Biol.

    (2002)
  • V. Angeli et al.

    Peroxisome proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response

    J. Immunol.

    (2003)
  • V.R. Babaev et al.

    Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice

    Arterioscler. Thromb. Vasc. Biol.

    (2005)
  • J. Barlic et al.

    Oxidized lipid-driven chemokine receptor switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary artery smooth muscle cells through a peroxisome proliferator-activated receptor gamma-dependent pathway

    Circulation

    (2006)
  • B.P. Barna et al.

    Depressed peroxisome proliferator-activated receptor gamma (PPargamma) is indicative of severe pulmonary sarcoidosis: possible involvement of interferon gamma (IFN-gamma)

    Sarcoidosis Vasc. Diffuse Lung Dis.

    (2006)
  • L. Benayoun et al.

    Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling

    Am. J. Respir. Crit. Care Med.

    (2001)
  • M.A. Birrell et al.

    PPAR-gamma agonists as therapy for diseases involving airway neutrophilia

    Eur. Respir. J.

    (2004)
  • C. Boileau et al.

    The peroxisome proliferator-activated receptor gamma agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: in vivo protective effects mediated through the inhibition of key signaling and catabolic pathways

    Arthritis Rheum.

    (2007)
  • T.L. Bonfield et al.

    Peroxisome proliferator-activated receptor-gamma is deficient in alveolar macrophages from patients with alveolar proteinosis

    Am. J. Respir. Cell Mol. Biol.

    (2003)
  • R.P. Brun et al.

    Differential activation of adipogenesis by multiple PPAR isoforms

    Genes Dev.

    (1996)
  • A. Castrillo et al.

    Inhibition of IkappaB kinase and IkappaB phosphorylation by 15-deoxy-Delta(12,14)-prostaglandin J(2) in activated murine macrophages

    Mol. Cell Biol.

    (2000)
  • A. Chawla et al.

    PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation

    Nat. Med.

    (2001)
  • R.B. Clark et al.

    The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses

    J. Immunol.

    (2000)
  • D.A. Culver et al.

    Peroxisome proliferator-activated receptor gamma activity is deficient in alveolar macrophages in pulmonary sarcoidosis

    Am. J. Respir. Cell Mol. Biol.

    (2004)
  • R. Cunard et al.

    Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors

    J. Immunol.

    (2002)
  • S. Cuzzocrea et al.

    The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2) attenuates the development of acute and chronic inflammation

    Mol. Pharmacol.

    (2002)
  • Cited by (135)

    • Protective effects and mechanisms of psoralidin against adriamycin-induced cardiotoxicity

      2022, Journal of Advanced Research
      Citation Excerpt :

      PPARγ agonists and antagonists have been used in many pharmacological and pathological studies. Studies have shown that PPARγ plays an important role in regulating free radicals, anti-inflammatory drugs and immune responses [42,43]. Moreover, knockout or inhibition of PPARγ in mice increased sensitivity to oxidative stress.

    • Anti-inflammatory effects of an optimized PPAR-γ agonist via NF-κB pathway inhibition

      2020, Bioorganic Chemistry
      Citation Excerpt :

      Some studies have reported that PPAR-γ protein can be expressed in macrophages, and that activated PPAR-γ translocates to the nucleus and binds NF-κB. Binding with PPAR-γ leads to NF-κB inhibition, thereby inhibiting the transcription of pro-inflammatory mediators such as iNOS, COX, TNF-α, and IL-6 [23]. Here, we used western blot analysis to assess the protein level of PPAR-γ translocated to the nucleus through activation by (+)-(R,E)-5f.

    View all citing articles on Scopus
    View full text