ReviewThe many faces of PPARγ: Anti-inflammatory by any means?
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).
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