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(Journal of Leukocyte Biology. 2002;71:388-400.)
© 2002 by Society for Leukocyte Biology

The role of PPARs in inflammation and immunity

Robert B. Clark

Division of Rheumatic Diseases, Department of Medicine, University of Connecticut Health Center, Farmington

Correspondence: Robert B. Clark, M.D., Division of Rheumatic Diseases, Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. E-mail: rclark{at}nso2.uchc.edu


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ABSTRACT
 
The family of transcription factors termed peroxisome proliferator-activated receptors (PPARs) has recently been the focus of much interest for their possible role in the regulation of inflammation and immune responses. PPAR{alpha} and PPAR{gamma} have been implicated in the regulation of macrophage and endothelial cell inflammatory responses. Although PPAR activation has generally been shown to have anti-inflammatory effects, opposite effects have been noted, and results often appear to depend on the ligands being used and the inflammatory parameters being measured. Recently, my laboratory and others have described a role for PPAR{gamma} in the responses of T lymphocytes. Ligands for PPAR{gamma} have been found to inhibit proliferation of activated T cells, and this appears to involve inhibition of IL-2 secretion and/or the induction of apoptosis. However, one problem in the interpretation of many of the studies of PPAR{gamma}, inflammation, and immunity is that ligands thought to be specific for PPAR{gamma} may have regulatory effects on inflammatory parameters that are PPAR{gamma}-independent. Future studies of the role of the PPARs in inflammatory and immune responses should include further studies of T cells, T-cell subsets, and dendritic cells but will have to re-examine the issue of PPAR specificity of the ligands being used. This may require further knockout studies and technology, together with the identification of endogenous and perhaps more specific synthetic PPAR ligands.

Key Words: T cells • macrophages • endothelial cells • thiazolidinediones


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INTRODUCTION
 
Until recently, the family of transcription factors termed peroxisome proliferator-activated receptors (PPARs) was believed to regulate genes predominantly associated with lipid and glucose metabolism. However, understanding the role played by PPARs in the regulation of inflammation and immunity is evolving rapidly. In this review, we will examine the role of PPARs in inflammation and immunity, focusing primarily on the role played by PPAR{alpha} and the newly described role of PPAR{gamma} in T-cell biology.


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THE PPAR FAMILY OF NUCLEAR RECEPTORS
 
Peroxisomes are subcellular organelles found in most plant and animal cells that perform diverse metabolic functions including H2O2-based respiration, ß-oxidation of fatty acids, and cholesterol metabolism. In rodents, a large class of structurally diverse industrial and pharmaceutical chemicals including herbicides, industrial solvents, and hypolipidemic drugs leads to significant increases in the size and number of peroxisomes in liver, liver hypertrophy, liver hyperplasia, hepatocarcinogenesis, and transcription of genes encoding peroxisomal enzymes. The structurally diverse compounds that induce these effects are termed peroxisome proliferators. In 1990, a nuclear receptor that was transcriptionally activated by peroxisome proliferators was identified [1 ]. Because the peroxisome proliferators were initially demonstrated to activate but not to directly bind this receptor, the receptor was named PPAR.

It is now known that PPARs are a family of transcription factors belonging to the nuclear receptor superfamily. PPARs regulate numerous genes through ligand-dependent transcriptional activation and repression, and until recently, the genes regulated were believed to be those predominantly associated with lipid metabolism [2 3 4 ]. Three different members of the PPAR family have been identified, encoded by separate genes: PPAR{alpha}, PPAR{delta} (also called beta or NUC-1), and PPAR{gamma} [5 6 7 8 ]. These three isotypes exhibit distinct patterns of tissue distribution and differ in their ligand-binding domains. PPAR{delta} is expressed ubiquitously and binds some of the same ligands as PPAR{alpha}, however its function remains unclear. PPAR{alpha} and PPAR{gamma} will be discussed in greater detail below.


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GENERAL PHYSIOLOGY OF PPARs
 
Like other members of the nuclear receptor superfamily, PPARs possess a central DNA-binding domain that recognizes DNA sequences, termed PPAR-response elements (PPREs), in the promoter regions of their target genes. PPARs heterodimerize with another member of the nuclear-receptor superfamily, the retinoid X receptors (RXR), and the transcription regulation of target genes by PPARs is actually achieved through the binding of these PPAR-RXR heterodimers to PPREs [2 , 3 , 9 , 10 ]. RXR also exists in multiple isoforms, RXR{alpha}, ß, and {gamma}, and like the PPARs, have a variable tissue distribution [11 , 12 ]. RXR isoforms are activated by 9-cis retinoic acid [2 ]. It is not known if any one of the particular RXR isoforms preferentially binds one or more of the PPAR isoforms.

RXR also forms heterodimers with other members of the nuclear receptor superfamily, and these interactions influence the PPAR-regulated transcriptional activation because of the competition among various RXR heterodimerization partners for RXR [4 ]. In the presence of ligands for PPAR, the PPAR:RXR heterodimer does not require that 9-cis retinoic acid be present for transcriptional activation. However, when combined as PPAR:RXR heterodimer, PPAR ligands and 9-cis retinoic acid can act synergistically on PPAR responses [2 ]. The different heterodimers of RXR (e.g., PPAR:RXR) allow for specific responses by binding to highly specific sequences in the promoter regions of the genes they transactivate [10 ].

Although the PPAR:RXR dimer is the focus for determining specific gene transcription on ligand activation, transactivation of a particular gene actually requires a large complex of proteins [13 , 14 ]. Thus, the regulation of PPAR-regulated transcriptional activation is made more complex by the involvement of coactivators and corepressors [15 , 16 ]. In the inactivated state, the PPARs are believed to be in complexes bound with corepressor proteins. In this state, in some but not all cell types, PPARs may have a cytoplasmic rather than a nuclear location [17 , 18 ]. Upon ligand activation, PPARs dissociate from corepressors and recruit coactivators, including the PPAR-binding protein [15 ] and the steroid receptor coactivator-1 [16 ], and can translocate from the cytoplasm to the nucleus [18 ].


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PPAR{alpha}—GENERAL PHYSIOLOGY
 
PPAR{alpha} was the first member of the family identified, and it is believed to be solely responsible for the effects of the peroxisomal proliferators described above [1 ]. PPAR{alpha} expression is relatively high in hepatocytes, heart, enterocytes, muscle, and the kidney. PPAR{alpha} regulates genes involved in the ß-oxidation of fatty acids and lipoprotein metabolism. Using PPAR{alpha}-deficient mice, this receptor was shown to be involved in high-density lipoprotein and triglyceride metabolism and in hepatic regulation of apolipoprotein and fatty acid ß-oxidation enzyme expression [19 , 20 ]. In addition to the structurally diverse compounds described above as peroxisomal proliferators, fibrates (used as drugs for the reduction of high triglyceride levels), specific fatty acids, and eicosanoids also can act as ligands for PPAR{alpha} [21 ]. In studies involving PPAR{alpha} and inflammation/immune responses, the relevant ligands studied most frequently have been the naturally occurring ligand, leukotriene B4 (LTB4), and the synthetic ligands, fenofibrate and Wyeth-14,643.


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PPAR{gamma}—GENERAL PHYSIOLOGY
 
PPAR{gamma} was characterized originally as a key regulator of adipocyte differentiation and lipid metabolism [7 , 22 23 24 ]. PPAR{gamma} expression is directed by different promoters, leading to three PPAR{gamma} isoforms [25 , 26 ]. Until recently, it had been believed that PPAR{gamma}1 isoform expression was restricted to liver, adipocytes, and a few other cell types and that the PPAR{gamma}2 isoform was expressed predominantly in adipocytes [7 , 22 ]. It is now clear that PPAR{gamma} is also found in other cell types including fibroblasts, myocytes, breast cells, the white and red pulp of rat spleen, human bone-marrow precursors, and macrophages/monocytes [27 , 28 ]. In addition, PPAR{gamma} has been shown in macrophage foam cells in atherosclerotic plaques [29 , 30 ]. An important role for PPAR{gamma} in glucose metabolism was identified when it was demonstrated that a class of antidiabetic drugs, the thiazolidinediones, were high-affinity PPAR{gamma} ligands [31 ]. The thiazolidinediones were developed originally for the treatment of type-2 diabetes on the basis of their ability to lower glucose levels (and levels of circulating fatty acids) in rodent models of insulin resistance. The finding that the thiazolidinediones mediate their therapeutic effects through direct interactions with PPAR{gamma} established PPAR{gamma} as a key regulator of glucose and lipid homeostasis [32 ]. Despite being described initially as a regulator of lipid and glucose metabolism, PPAR{gamma} has also been demonstrated recently to have a role in cell proliferation and malignancy. Ligands for PPAR{gamma} have been shown to mediate positive and negative effects on cell proliferation and malignancy [16 , 33 34 35 36 37 38 39 ].

In addition to the thiazolidindione class of antidiabetic drugs, a variety of nonsteroidal anti-inflammatory drugs also can function as PPAR{gamma} ligands, although the latter have relatively low affinity [40 ]. The prostaglandin D2 (PGD2) dehydration product PGJ2 was the first endogenous ligand discovered for PPAR{gamma} [41 , 42 ]. The additional PGD2 dehydration product, 15-deoxy-{Delta}12,14-PGJ2 (15d-PGJ2), is also a naturally occurring substance that binds directly to PPAR{gamma} and is a potent ligand for PPAR{gamma} activation [41 , 42 ]. In addition, components of oxidized low-density lipoproteins (OxLDL), including 9- and 13-hydroxyoctadecadienoic acid (HODE), have been described as endogenous PPAR{gamma} activators [43 ]. 12- and 15-Hydroxyeicosatetaenoic acid (HETE) are also PPAR{gamma} ligands [44 ]. Although many naturally occurring fatty acids and their metabolites can activate PPAR{gamma}, they bind with relatively low affinities and must be added to cells at high concentrations to stimulate transcription. It has been difficult therefore to establish the physiological relevance of any of these substances as actual in vivo regulators of PPAR{gamma} [45 ]. For a more detailed review of the structure and physiology of PPARs, see Ricote et al. [46 ].


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PPAR{alpha} IN INFLAMMATION AND IMMUNE RESPONSES
 
In vivo studies of inflammatory/immune functions of PPAR{alpha}
In vivo studies of the inflammatory/immune-related functions of PPAR{alpha} have yielded a somewhat muddled picture. In vivo evidence for a role of PPARs in inflammation was first suggested in studies using PPAR{alpha} knockout mice. PPAR{alpha} knockout mice are viable but lack responses to appropriate ligands (i.e., no peroxisome proliferation, no gene activation, no hepatomegaly) and exhibit abnormalities in triglyceride and cholesterol metabolism [47 , 48 ]. In an early study, inflammatory responses were induced in vivo in the ears of mice using LTB4, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), or arachidonic acid, and the responses of wild-type mice were compared with that of PPAR{alpha} null mice [49 ]. Inflammation induced by LTB4 or arachidonic acid, but not TPA, was prolonged in PPAR{alpha} null mice. In light of the fact that anything affecting the degradation rate of LTB4 can affect the extent and duration of an inflammatory reaction, and given that direct interaction between PPAR{alpha} and LTB4 induces enzymes for fatty acid degradation and as such increases the catabolism of LTB4, the investigators proposed that LTB4 induces its own catabolism via PPAR{alpha} activation [49 ].

In contrast to the anti-inflammatory effects of PPAR{alpha} activation suggested by the former study, another in vivo study involved the treatment of CD-1 mice with fenofibrate or Wy14,643. Such treated mice had fivefold higher lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNF-{alpha}) plasma levels and a significantly lower, 50% lethal dose than control mice [50 ]. Using PPAR{alpha} null mice, this result was confirmed to be mediated by PPAR{alpha} [50 ]. In these same studies, however, peritoneal macrophages from wild-type mice treated with Wy14,643 showed modestly decreased (rather than increased) TNF expression in vitro. Thus, the systemic effects of the PPAR{alpha} agonists represent a complicated mixture of effects [50 ]. Finally, a further in vivo study of the inflammatory/immune relevance of PPAR{alpha} involved the aging process [51 ]. Previously, it had been shown that in aged mice, oxidative stress-induced, redox-regulated transcription of nuclear factor-{kappa}B (NF-{kappa}B) becomes constitutive in many tissues. It was then demonstrated that the administration of PPAR{alpha} agonists to aged mice restored the cellular-redox balance and resulted in an elimination of the constitutively active NF-{kappa}B and in a resultant loss in spontaneous inflammatory cytokine production [51 ]. Furthermore, aged PPAR{alpha} null mice did not show these changes after administration of PPAR{alpha} agonists. Finally, aged C57BL/6 mice were found to express reduced PPAR{alpha} transcripts that increased with the addition of PPAR{alpha} ligands. Thus, these investigators suggested that PPAR{alpha} may play a role in the evolution of the oxidative stress excesses observed in aging [51 ].

In vitro studies of inflammatory/immune functions of PPAR{alpha}
The majority of the investigations of the role of PPAR{alpha} in inflammation/immunity involves in vitro investigations. It has been demonstrated that PPAR{alpha} is expressed in murine [50 , 52 ] and human monocyte-macrophages [53 ]. Also relevant to its function in inflammation/immunity, PPAR{alpha} has been found to be expressed in various type of human endothelial cells (ECs) [54 55 56 ]. However, PPAR{alpha} is not expressed in murine-dendritic cells [57 ], in human mast cells [58 ], or in murine bone marrow-derived mast cells [59 ].

Monocytes-macrophages
Using the activated RAW264.7 murine-macrophage cell line, proinflammatory and anti-inflammatory effects of PPAR{alpha} ligands have been demonstrated [52 ]. It was found that the two naturally occurring PPAR{alpha} ligands, LTB4 and 8(S)-HETE, stimulated nitric oxide synthase (NOS) activity. However, the synthetic ligand Wy14,643 inhibited NOS activity [52 ]. The difference between the natural and synthetic ligands was postulated to be a result of the low specificity (and thus multiple effects) of the natural compounds compared with the more selective effects of the synthetic compounds [60 ]. In human monocytes, PPAR{alpha} has been shown to be constitutively present in undifferentiated monocytes and to reside in the cytoplasm [53 ]. Ligands for PPAR{alpha} were not able to induce apoptosis of inactivated (differentiated) macrophages but did cause apoptosis of activated macrophages [53 ]. An additional study demonstrating the anti-inflammatory effects of PPAR{alpha} ligation involved the THP-1 human monocytic leukemia cell line [61 ]. In this study, fenofibrate did not affect the LPS-induced secretion of interleukin (IL)-8 but induced significant down-regulation of LPS-induced secretion of matrix metalloprotein-9 (MMP-9).

ECs
Several studies have suggested a role for PPAR{alpha} in the down-regulation of EC-inflammatory responses. An early event in inflammation is the expression of specific adhesion molecules on the surface of ECs, which subsequently bind leukocytes. PPAR{alpha} was found to be expressed in human aortic ECs (HAECs), and WY14,643 was demonstrated to partially inhibit the phorbol 12-myristate 13-acetate (PMA)- and LPS-induced expression of vascular cell-adhesion molecule-1 (VCAM-1) on HAECs and had no effect on the expression of intercellular adhesion molecule-1 (ICAM-1), E-selectin, or neutrophil-like HL-60 cell-binding to activated HAECs [54 ]. In a confirmatory study, human carotid artery ECs were found to express PPAR{alpha} [56 ]. When these ECs were precultured with Wy14,643 or fenofibrate, TNF-{alpha}-induced VCAM-1 expression was inhibited in a time- and concentration-dependent manner (an effect not seen with PPAR{gamma} agonists) [56 ]. PPAR{alpha} has also been found to be expressed in human aortic smooth-muscle cells, and in these cells, PPAR{alpha} ligands inhibit IL-1-induced production of IL-6 and PG and inhibit the expression of cyclooxygenase-2 (COX-2) [62 ]. In hyperlipidemic patients, fenofibrate decreases the plasma concentrations of IL-6, fibrinogen, and C-reactive protein [62 ]. Confirmatory experiments demonstrated that aortic explants from PPAR{alpha} null mice stimulated with LPS secreted increased amounts of IL-6 and that fibrates decreased IL-6 mRNA levels in LPS-stimulated aortas from wild-type but not from PPAR{alpha} null mice [63 ]. In human aortic smooth-muscle cells, fibrates were found to inhibit IL-1-induced IL-6 gene expression [63 ]. In contrast to the majority of studies that demonstrate anti-inflammatory, regulatory effects of PPAR{alpha} in ECs, another study of HAECs supported a proinflammatory role for PPAR{alpha}. This proinflammatory effect was seen in the mediation of EC production of monocyte-chemotactic activity in response to lipids [55 ]. In addition, Wy14,643 was found to stimulate HAECs to synthesize IL-8 and monocyte-chemoattractant protein-1 (MCP-1).

Mechanisms of PPAR{alpha} effects
The mechanisms of the anti- or proinflammatory effects of PPAR{alpha} have been studied extensively. As recently summarized by Delerive et al. [64 ], many mechanisms have been described possibly underlying the anti-inflammatory effects of PPAR{alpha} seen in macrophage/monocytes and ECs. For example, direct protein-protein interactions between PPAR{alpha} and activated protein-1 (AP-1) and NF-{kappa}B proteins have been invoked as mechanisms of negative regulation of inflammatory responses [63 ]. In addition, by up-regulating antioxidant enzyme activities, PPAR{alpha} ligands reduce the oxidative stress and thus may inhibit NF-{kappa}B activation [51 ]. Finally, Delerive et al. [64 ] have demonstrated that fibrates induce I{kappa}B{alpha} expression in a PPAR{alpha}-dependent manner. This induction results in an inhibition of NF-{kappa}B DNA binding, leading to a sharp reduction of the p65-mediated gene activation.

Conclusion—PPAR{alpha} effects on inflammation/immune responses
Based on in vivo and in vitro studies with different cell types, PPAR{alpha} ligands appear to have a largely anti-inflammatory effect. However, the effects have been found to vary, and in some studies, proinflammatory effects have been demonstrated (Table 1 ). It seems that in monocyte/macrophages, the major effects appear to be apoptotic for activated macrophages and an inhibition of a subset of macrophage proinflammatory cytokines. In ECs, the major effects appear to be a decrease in the vascular expression of VCAM-1, but in contrast, a proinflammatory role for PPAR{alpha} has been shown in the mediation of EC production of monocyte-chemotactic activity in response to lipids. In vivo, PPAR{alpha} appears to play an anti-inflammatory role in LTB4-mediated inflammation, perhaps through a role in the degradation of the LTB4, while other in vivo studies reveal proinflammatory effects of PPAR{alpha} ligands, including an elevation of plasma TNF-{alpha} and a decrease in LD50 in response to LPS. Finally, PPAR{alpha} may play a role in the regulation of aging-related abnormalities in inflammation. The majority of these effects on inflammation and immunity appear to be mediated through effects on NF-{kappa}B, but other pathways are also likely involved.


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  		Table 1. PPAR{alpha} and Inflammation


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PPAR{gamma} IN INFLAMMATION AND IMMUNITY
 
Until recently, evidence for PPAR{gamma} expression and function in the immune system had been limited. Greene et al. [28 ] screened a human bone-marrow cDNA library and found that peripheral blood lymphocytes expressed only a truncated PPAR{gamma} transcript, which the authors believed could not encode all of the PPAR{gamma} functional domains. Braissant et al. [27 ] studied PPAR expression in rat tissues using in situ hybridization and immunohistochemistry and described the expression of PPAR{gamma} in the white and red pulp of the rat spleen as well as in the Peyer’s patches of the rat. Finally, in relating PPARs to inflammation, Gilroy et al. [65 ], studying COX-2 inhibitors in a rat model of carrageenin-induced pleural inflammation, presented evidence for an anti-inflammatory role of PGD2 and 15d-PGJ2, suggesting a possible role for PPAR{gamma} in inflammation.

Role of PPAR{gamma} in inflammatory and immune functions of monocytes/macrophages
One of the earliest findings associating PPARs and macrophages was that PPAR{gamma} was highly expressed in macrophage-derived foam cells of human and murine atherosclerotic lesions [29 , 30 , 66 ]. Subsequently, it has been demonstrated that PPAR{gamma} is expressed in human and murine monocytes/macrophages. Functionally, PPAR{gamma} has been shown to play a role in the differentiation and activation of monocytes and in the regulation of inflammatory activities [43 , 46 , 66 67 68 ] (Table 2 ).


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  		Table 2. PPAR{gamma} and Immune Response of Macrophages

Expression of PPAR{gamma} in monocytes/macrophages
Many studies have suggested a link between the state of macrophage/monocyte differentiation or activation and PPAR{gamma} expression. In the mouse, PPAR{gamma} is expressed at low levels in nonactivated monocytes/macrophages, and higher levels are expressed in activated peritoneal macrophages [30 ]. A similar relationship between the state of differentiation and activation and PPAR{gamma} expression has been described for human peripheral blood monocytes [53 ]. Furthermore, activation of monocyte/macrophages or monocyte lines with phorbol esters, OxLDL, macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage CSF (GM-CSF) induced an increased expression of PPAR{gamma} [30 , 53 ]. In recent studies, which have begun to link monocyte/macrophage PPAR{gamma} to the adaptive immune system, Huang et al. [69 ] investigated the effects of cytokines on macrophage PPAR{gamma} expression and function. They found that IL-4 strongly induced PPAR{gamma}1 expression in resident peritoneal macrophages and human peripheral blood monocytes and that IL-4 not only up-regulated PPAR{gamma} expression in macrophages but also enhanced the activation of PPAR{gamma} via the production of the endogenous PPAR{gamma} ligands, 13-HODE, 12-HETE, and 15-HETE [69 ]. As such, this study may represent an important documentation of the in vivo function of endogenous PPAR{gamma} ligands. In addition to PPAR{gamma} expression being up-regulated after macrophage activation, evidence suggests that PPAR{gamma} activation can itself lead to monocyte differentiation in a cell line [66 ]. Finally, given the relevance of dendritic cells in the initiation, and perhaps in the regulation, of adaptive immune responses, it is important to note that one study has demonstrated the expression of PPAR{gamma} (but not PPAR{alpha}) in immature and mature murine, spleen-derived, dendritic cells [57 ]. Furthermore, a thiazolidinedione (rosiglitazone) did not interfere with the in vitro maturation of dendritic cells nor did it modify their ability to activate naive T cells in vivo. However, PPAR{gamma} activators were found to down-modulate the CD-40-induced secretion of IL-12 [57 ]. Additional studies of PPAR expression and function in dendritic cells will now be needed to confirm these results.

Role of PPAR{gamma} in monocytes/macrophage inflammatory responses
Many studies have demonstrated that PPAR{gamma} ligands inhibit macrophage-inflammatory responses. Previously, this subject has been well reviewed [46 , 60 ] and will be summarized briefly here. The anti-inflammatory effects of PPAR{gamma} activation have been demonstrated with human and murine monocyte/macrophages and monocyte/macrophage lines. Activation of macrophages normally leads to the secretion of several different proinflammatory mediators. Treatment with 15d-PGJ2 or thiazolidinediones has been found to inhibit the secretion of many of these mediators (including gelatinase B, IL-6, TNF-{alpha}, and IL-1ß) and also to reduce the induced expression of inducible NOS (iNOS) and the transcription of the scavenger receptor-A gene [67 , 68 ]. In addition, Azuma et al. [70 ] demonstrated that dPGJ2 as well as 13-HODE inhibited LPS-induced IL-10 and IL-12 production by macrophages. Finally, Chinetti et al. [53 ] have demonstrated that in human monocyte/macrophages, ligand activation of PPAR{gamma} (but not PPAR{alpha}) resulted in apoptosis of nonactivated macrophages and that both PPAR{alpha} and PPAR{gamma} ligands induced apoptosis of macrophages that had been activated.

Although many studies have demonstrated inhibitory effects, others suggest that PPAR{gamma} ligands lead to a more complex pattern of macrophage-inflammatory responses. PPAR{gamma} ligands have been found to stimulate the expression of the proinflammatory receptors CD14 and CD11b/CD18 and to increase expression of class B scavenger receptors (CD36 and SR-B1) [66 , 71 , 72 ]. Although human peripheral blood monocyte-stimulated production of TNF-{alpha} and IL-6 was inhibited by 15d-PGJ2, four other high-affinity PPAR{gamma} ligands failed to affect cytokine production [73 ]. In vivo studies with db/db mice challenged with LPS and treated with a thiazolidinedione showed no suppression of cytokine production and, in fact, showed higher blood levels of TNF-{alpha} and IL-6 than the controls [73 ]. Other examples of the complexity of the effects shown for PPAR{gamma} activation include the finding that rosiglitazone (and fibrates) failed to modulate LPS-induced secretion of IL-8 while down-regulating MMP-9 in a human monocytic line [61 ] and that 15d-PGJ2 induced IL-8 gene expression and suppressed MCP-1 but did not affect expression of RANTES (regulated on activation, normal T expressed and secreted) in human monocyte/macrophages [74 ]. The latter investigators also showed that 15d-PGJ2 potentiated LPS-induced but suppressed PMA-induced expression of IL-8 mRNA. The effects of PPAR{gamma} ligands on monocyte/macrophage inflammatory responses are obviously not simple and among other parameters, appear to depend on the PPAR ligands used, the mode by which monocytes/macrophages are activated, and the inflammatory responses measured. Finally, there have been no studies describing the effects of PPAR activation on the antigen-presenting function of macrophage/monocytes, and such studies could prove valuable in understanding the role of PPAR in the adaptive immune response.

PPAR{gamma} and ECs
The other major cell type studied relating PPAR{gamma} to inflammation and immunity is the EC. ECs play an important role in homing inflammatory and immune-relevant cells and thus in the localization of inflammatory and immune responses. ECs from various sources have been shown to express PPAR{gamma}, and agonists have been shown to mediate effects on cell survival, surface-protein expression, and cytokine and chemokine expression. As with the studies of monocyte/macrophages, the results of these endothelial studies, when taken together, do not present an easily unified picture (Table 3 ). Bishop-Bailey and Hla [75 ] demonstrated that ECs expressed PPAR{alpha}, {delta}, and {gamma} and that 15d-PGJ2 and a thiazolidinedione induced endothelial apoptosis. Anti-inflammatory effects shown include a thiazolidinedione-induced decrease in the levels of IL-8 and MCP-1 in HAECs [55 ] and an inhibition by PPAR{gamma} ligands of the interferon-{gamma} (IFN-{gamma})-induced expression of CXC chemokines but not a CC chemokine [76 ]. The latter investigators suggested that PPAR{gamma} ligands might thus attenuate the recruitment of activated T cells at sites of T-helper cell type 1 (Th1)-mediated inflammation [76 ]. However, a dual effect of troglitazone on human vascular ECs was demonstrated in which there was an increase in basal ICAM-1 expression but an inhibition of TNF-{alpha}-induced ICAM-1 expression [77 ]. Jackson et al. [54 ] showed that in HAECs, ICAM-1 induction by PMA was unaffected by any of the PPAR ligands. They found, however, that PPAR{alpha} and {gamma} activators (although not BRL49653) partially inhibited the induced expression of VCAM-1. In contrast, Marx et al. [56 ] reported that PPAR{gamma} agonists did not inhibit expression of TNF-{alpha}-induced VCAM-1 as did PPAR{alpha} agonists. Overall, a consistent and integrated picture of the effect of PPAR{gamma} ligands on the inflammatory/immune aspects of endothelial function awaits further study.


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  		Table 3. PPAR{gamma} and Endothelial Cells/Endothelial Cell Lines


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PPAR AND INFLAMMATION/IMMUNITY IN DISEASE AND DISEASE MODELS
 
The relevance of PPAR{gamma} has been studied in several human autoimmune diseases and animal models of autoimmune diseases. Kawahito et al. [78 ] demonstrated that synovial tissue expressed PPAR{gamma} in patients with rheumatoid arthritis (RA). PPAR{gamma} was found to be highly expressed in macrophages, and modest expression was noted in synovial-lining fibroblasts and ECs. Activation of PPAR{gamma} by 15d-PGJ2 and troglitazone induced RA synoviocyte apoptosis in vitro [78 ].

Alzheimer’s disease (AD) is characterized by the extracellular deposition of ß-amyloid fibrils within the brain and the activation of microglial cells associated with the amyloid plaque. The activated microglia subsequently secrete a diverse range of inflammatory products [79 ]. Kitamura et al. [80 ] assessed the occurrence of COX-1, COX-2, and PPAR{gamma} in normal and AD brains using specific antibodies and found increased expression of these moieties in AD brains. Nonsteroidal, anti-inflammatory drugs (NSAIDs) have been shown to be efficacious in reducing the incidence and risk of AD and in delaying disease progression [81 ]. Combs et al. [79 ] demonstrated that NSAIDs, thiazolidinediones, and PGJ2, all of which are PPAR{gamma} agonists, inhibited the ß-amyloid-stimulated secretion of inflammatory products by microglia and monocytes. PPAR{gamma} agonists were shown to inhibit the ß-amyloid-stimulated expression of the genes for IL-6 and TNF-{alpha} and the expression of COX-2 [79 ]. Finally, Heneka et al. [82 ] demonstrated that microinjection of LPS and IFN-{alpha} into rat cerebellum induced iNOS expression in cerebellar granule cells and subsequent cell death. Coinjection of PPAR{gamma} agonists (including troglitazone and 15d-PGJ2) reduced iNOS expression and cell death, whereas coinjection of a selective COX inhibitor had no effect. Overall, work in AD seems to suggest that PPAR{gamma} agonists can modulate inflammatory responses in the brain and that NSAIDs may be helpful in AD as a result of their effect on PPAR{gamma}.

Several studies have investigated the role of PPAR{gamma} ligands in modifying animal models of autoimmune diseases. Su et al. [83 ] showed that in a mouse model of inflammatory bowel disease, thiazolidinediones markedly reduced colonic inflammation. These authors proposed that this effect might be a result of a direct effect on colonic epithelial cells, which express high levels of PPAR{gamma} and can produce inflammatory cytokines. Kawahito et al. [78 ] demonstrated that intraperitoneal administration of the PPAR ligands, 15d-PGJ2 and troglitazone, ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in rats. Nino et al. [84 ] examined the effect of a thiazolidinedione on experimental allergic encephalomyelitis and found that this treatment attenuated the inflammation and decreased the clinical symptoms in this mouse model of multiple sclerosis. Finally, Reilly et al. [85 ] demonstrated that renal glomerular mesangial cells are important modulators of the inflammatory response in lupus nephritis, secreting, when activated, inflammatory mediators including NO and cyclooxygenase products, thus perpetuating the local inflammatory response. Mesangial cells isolated from the lupus-prone MRL/lpr mice or control Balb/c mice were stimulated, and it was found that the MRL/lpr mesangial cell cultures did not increase PGJ2 production as did the cells from Balb/c mice. This suggested an abnormality in MRL/lpr mice in a normally present endogenous, anti-inflammatory pathway mediated by PGJ2, perhaps working through PPAR{gamma}. NO production from the mesangial cells of both mouse strains was found to be blocked by PGJ2 and a thiazolidinedione. Given the above studies, the relevance of PPARs and the utility of treatment with PPAR agonists in diseases with an inflammatory or autoimmune pathogenesis will likely continue to remain a research focus.


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THE ROLE OF PPAR{gamma} IN T CELLS
 
It is noteworthy that even in the studies of autoimmune disease models, the question of PPAR{gamma} expression and function in T cells had not been raised. Recently, my laboratory was the first to describe the expression and function of PPAR{gamma} in T lymphocytes [86 ]. We demonstrated for the first time that murine T cells express PPAR{gamma}1, but not PPAR{gamma}2. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, SJL-derived Th1 clones [clones MM4 and B48, specific for bovine myelin basic protein (BMBP)] were found to express significant levels of PPAR{gamma}1. Using RT-PCR, we have also found that freshly isolated T-cell-enriched splenocytes from SJL mice express PPAR{gamma}1 mRNA but not PPAR{gamma}2. The PPAR{gamma} expressed by the T-cell clones and by freshly isolated C57BL/6 T-cell-enriched splenocytes was shown to be of functional significance. This functional significance was demonstrated through the use of two PPAR{gamma} ligands, 15d-PGJ2 and a thiazolidinedione, ciglitazone.

My laboratory demonstrated that 15d-PGJ2 and ciglitazone mediate significant inhibition of the antigen (BMBP)-stimulated responses of the T-cell clones and mediate significant inhibition of the anti-CD3 antibody-stimulated proliferative responses of the T-cell clones and the freshly isolated T-cell-enriched splenocytes (Tables 4 5 6 7 ). This inhibition was directed at the level of the T cell, given that T-cell stimulation with immobilized anti-CD3 antibody is a macrophage/antigen-presenting cell (APC)-independent response, and for the T-cell clones, this inhibition was observed in the absence of monocytes/macrophages. The inhibition of the responses of the T-cell-enriched splenocytes (Table 6) suggests that PPAR{gamma} is functionally relevant in freshly isolated T cells or becomes functionally relevant early in activation.


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  		Table 4. 15d-PGJ2 Inhibits Murine T Cell Clone Proliferative Responses


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  		Table 5. Ciglitazone Inhibits Murine T Cell Clone Proliferative Responses


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  		Table 6. Anti-CD3 Antibody-Stimulated Responses of T-Cell Enriched C57BL/6 Splenocytes


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  		Table 7. 15d-PGJ2 and Ciglitazone Inhibit Murine T Cell Clone IL-2 Secretion

In these studies, it was also demonstrated that the two ligands for PPAR{gamma} mediated inhibition of IL-2 secretion by the T-cell clones and did not inhibit IL-2-induced proliferation of such clones (Tables 4 5 and 7) . This lack of inhibition of the IL-2-induced proliferation is noteworthy for two reasons. First, it demonstrates that the inhibitory effects noted were not a result of toxic effects of 15d-PGJ2 or ciglitazone at the concentrations studied. Second, it suggests that PPAR{gamma}-ligand interaction may affect signaling pathways involved in the response to T-cell receptor stimulation but not pathways involved after IL-2-receptor ligation.

Soon after this study, Yang et al. [87 ] showed that PPAR{gamma} was also expressed in human peripheral blood T cells. In agreement with my findings in murine T cells, these investigators found that a thiazolidinedione, troglitazone (20–40 µM), and 15d-PGJ2 (1–10 µM) but not a PPAR{alpha} ligand inhibited phytohemagglutinin (PHA)-induced proliferation, IL-2 production, and IL-2 mRNA expression in human peripheral blood T cells in a dose-dependent manner. Then, they transfected PPAR{gamma}2 cDNA into Jurkat cells and found that transfected but not wild-type Jurkat cells (which express little detectable PPAR{gamma} mRNA) were inhibited in IL-2 secretion by PPAR{gamma} ligands. This effect was shown to be at least partially a result of PPAR{gamma} effects on IL-2 promoter activity. A PPAR{alpha} ligand did not inhibit IL-2 secretion, suggesting that PPAR{alpha} could not mediate this inhibition in Jurkat cells. Given the recent studies demonstrating that 15d-PGJ2 and the thiazolidinediones appear to mediate macrophage anti-inflammatory effects that are PPAR{gamma}-independent (see below), these T-cell transfection studies are important. They may indicate that in T cells, thiazolidinediones mediate their effects only through PPAR{gamma}-dependent pathways. Finally, Yang et al. [87 ] demonstrated that the activated PPAR{gamma} physically associates with the transcription factor nuclear factor of activated T cells (NFAT), thus blocking its DNA-binding and transcriptional activation of the IL-2 promoter. The activation and function of NFAT are known to be absolute requirements for IL-2 transcription [87 ].

More recently, Harris and Phipps [88 ] confirmed the expression of PPAR{gamma} in murine T cells. They demonstrated that naive and PMA-activated, ovalbumin-specific T cells from T-cell-receptor transgenic mice expressed PPAR{gamma}1 mRNA and protein. The investigators also found that their T cells did not express mRNA for PPAR{gamma}2. Immunohistochemical analysis revealed that PPAR{gamma} staining in naive cells was predominantly cytoplasmic with some perinuclear staining. In activated T cells, staining also included a nuclear component and was more intense overall than in naive T cells. When T cells were stimulated (with PMA and ionomycin or antigen and APCs) in the presence of 15d-PGJ2 or troglitazone, these investigators also noted an inhibition of proliferation. However, they found that this inhibition of proliferation was accompanied by significant decreases in cell viability. The latter was demonstrated to be a result of apoptosis of the T cells and occurred only when cells were treated with PPAR{gamma} but not PPAR{alpha} agonists. 15d-PGJ2 mediated these effects in a dose range of 3–100 µM. The thiazolidinediones, ciglitazone and troglitazone, were effective in dose ranges of 25–100 µM. Finally, Harris and Phipps [88 ] also suggest that PPAR{gamma} may play a role in T-cell development, given that thymic-stromal cells express COX-1 and COX-2 enzymes, that inhibition of these enzymes interferes with positive selection [89 , 90 ], and that PGD synthase is produced by thymic-dendritic cells, suggesting that PGD2 and the J-series PGs may be present [91 ].

The demonstration of the expression and function of PPAR{gamma} in human and murine T cells now greatly expands the possible immunoregulatory role for PPAR{gamma}. Taken together with the effects of PPAR{gamma} ligands on macrophage function, the T-cell findings suggest that PPAR{gamma} may play a significant role in the regulation of the innate and adaptive immune response. (However, see the discussion below concerning the PPAR specificity of the macrophage effects noted.) Finally, although the T-cell studies agree on the functional role of PPAR{gamma} activation in inhibiting activated T-cell proliferation, the mechanism(s) of this inhibition is not yet totally clear. Our studies [86 ] and those of Yang et al. [87 ] suggest an inhibition of IL-2 secretion, and the studies of Harris and Phipps [88 ] suggest apoptosis as the mode of PPAR{gamma}-mediated T-cell regulation. However, our studies using IL-2-dependent murine T-cell clones may also involve cell death as a mode of regulation. Preliminary studies in my laboratory indicate that the addition of IL-2 at different times relative to PPAR{gamma} ligation may lead to different outcomes. These preliminary studies indicate that if the PPAR{gamma} ligands are removed, and exogenous IL-2 is added two days after rather than simultaneously with the addition of the higher concentrations of 15d-PGJ2 (5 µM) or ciglitazone (40 µM), our T-cell clones cannot be recovered and undergo cell death. Future studies in my laboratory will examine further the relationship between apoptosis and PPAR{gamma}-mediated T-cell effects.

Many other issues now await study regarding the relevance of PPAR{gamma} to T-cell biology. These issues include the mechanism(s) by which PPAR{gamma} ligands mediate the T-cell effects, as well as the possible differential expression and function of PPAR{gamma} in the many T-cell types and subtypes. Given the varied patterns of signaling pathways and cytokine secretion found in different subsets of T cells, I believe it is likely that PPAR{gamma} ligation will have pleiomorphic effects in different T-cell subsets. In vivo, it may be that PPAR{gamma} ligation plays an immunoregulatory role early in the initiation of T-cell immune responses as well as in inhibiting the recruitment of naive T cells into an ongoing immune response. It is possible that as additional endogenous ligands become known, they will be found to be involved in normal T-cell immunoregulatory processes. Finally, as discussed below, it will be crucial to document the true specificity of any ligands used in PPAR studies in T cells, and this will likely require T-cell-specific knockout technology.


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SPECIFICITY OF 15d-PGJ2 for PPAR{gamma}
 
As reviewed by Spiegelman [92 ], one problem with many of the experiments described above is that they used 15d-PGJ2 as a PPAR{gamma}-specific ligand. Many studies have suggested that 15d-PGJ2 may not be specific for PPAR{gamma} [93 94 95 96 ]. Another difficulty with many of these studies is that when more selective ligands (e.g., thiazolidinediones) were used, high concentrations—far exceeding those required to bind the receptor—were necessary to achieve the results described [97 ].

Recently, the issue of the specificity of 15d-PGJ2 for PPAR{gamma} has been at least partially clarified. NF-{kappa}B is a critical activator of genes involved in inflammation and immunity [98 ]. In this activation, the I{kappa}B kinase complex (IKK) phosphorylates the NF-{kappa}B inhibitors (I{kappa}B proteins) leading to their conjugation with ubiquitin and subsequent degradation. This then allows freed NF-{kappa}B dimers to translocate to the nucleus and induce target genes [98 ]. Rossi et al. [98 ] demonstrated that the cyclopentenone PGs, including 15d-PGJ2, directly inhibit and modify the IKK2 subunit of IKK. This, in turn, prevents the phosphorylation of the inhibitory I{kappa}B proteins that then target these proteins for ubiquitin conjugation and degradation [99 ]. This then prevents the activation of NF-{kappa}B. Similarly, Castrillo et al. [99 ] showed that in RAW 264.7 macrophage cells treated with LPS and IFN-{alpha}, incubation with 15d-PGJ2 resulted in a significant inhibition of IKK2 activity and an inhibition of the degradation of the inhibitory I{kappa}B proteins. This, in turn, caused a partial inhibition of NF-{kappa}B activity and an impaired expression of genes requiring NF-{kappa}B activation—such as type-2 NOS and cyclooxygenase 2 [99 ]. Finally Straus et al. [100 ] also confirmed these findings. These investigators demonstrated that 15d-PGJ2 inhibits NF-{kappa}B-dependent transcription by two PPAR{gamma}-independent pathways: covalent modifications of critical cysteine residues in IKK and the DNA-binding domains of NF-{kappa}B subunits. These studies have now clearly demonstrated that 15d-PGJ2 cannot be used to document effects that are mediated solely through PPAR{gamma}.


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STUDIES USING PPAR{gamma} NULL MACROPHAGES
 
Attempts to generate a PPAR{gamma}-deficient mouse have resulted in embryonic lethality. Recently, to overcome this, investigators have used two approaches to study PPAR{gamma} null macrophages: 1) using homologous recombination to create embryonic stem cells that are homozygous for a null mutation in the PPAR{gamma} gene, together with in vitro differentiation of embryonic stem cells into macrophages and 2) assessment (via PCR) of mature PPAR{gamma} null-macrophage representation in chimeric mice that were generated by the injection of PPAR{gamma}-deficient embryonic stem cells into wild-type blastocysts [97 , 101 ]. These studies have allowed for new insights into the role played by PPAR{gamma} in macrophage differentiation and function (including in inflammatory responses) and for new insights into the specificity of PPAR{gamma} ligands in macrophages. Studying PPAR{gamma} null macropages, Moore et al. [101 ] have demonstrated that PPAR{gamma} is neither essential for macrophage differentiation nor for such mature macrophage functions as phagocytosis and inflammatory cytokine production. PPAR{gamma} was found to be required for basal expression of CD36 but not for expression of the other major scavenger receptor, SR-A, responsible for uptake of modified lipoproteins. The absence of PPAR{gamma} was found to significantly reduce the cellular uptake and degradation of OxLDL. These authors also confirmed the requirement for PPAR{gamma} in the IL-4-induced increase in macrophage CD36 expression. However, PPAR{gamma}-deficient macrophages showed no difference from wild-type macrophages in expression of CD14 or other macrophage-specific surface markers and produced similar levels of TNF-{alpha} and IL-6 after LPS stimulation. This suggests a lack of PPAR{gamma} ligand involvement in the normal regulation of macrophage-cytokine secretion. PPAR{gamma} null macrophage-phagocytic activity was also similar to that seen in the wild-type macrophages. In addition, the effect of PPAR{gamma} ligands on PMA stimulation showed that in wild-type macrophages and the cell line RAW264.7, troglitazone increased IL-6 production, but this increase was not observed in PPAR{gamma}-deficient macrophages. Furthermore, 15d-PGJ2 inhibited PMA-induced IL-6 production in wild-type macrophages as well as in PPAR{gamma}-deficient macrophages, indicating that this inhibitory response is not dependent on PPAR{gamma}.

Chawla et al. [97 ], using PPAR{gamma} null macrophages, demonstrated that PPAR{gamma} is neither essential for nor substantially affects the development of the macrophage lineage in vitro and in vivo. In contrast, they showed that it is an important regulator of the scavenger receptor CD36. Most important, these investigators demonstrated that 15d-PGJ2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR{gamma}. They showed that PPAR{gamma} is required for positive effects of its ligands in modulating macrophage-lipid metabolism, but the inhibitory effects on cytokine production and inflammation may be PPAR{gamma}-independent. When macrophages were stimulated with LPS in the context of PPAR{gamma} ligands, the LPS-induced level of TNF-{alpha} and IL-6 did not differ between wild-type and PPAR{gamma}-deficient macrophages, and 15d-PGJ2 and thiazolidinediones inhibited the secretion of both cytokines equally in wild-type and deficient macrophages. To further confirm this, they stimulated macrophages with IFN-{gamma} and evaluated gene expression for iNOS and COX-2. The increase in mRNAs was equal between wild-type and PPAR{gamma}-deficient macrophages. Finally, the expression of these proinflammatory genes was inhibited by both ligands in wild-type and PPAR{gamma}-deficient macrophages.

Although there are plausible alternative interpretations for the results of these studies [102 ], and although it is possible that the PPAR{gamma}-independent effects of the thiazolidinediones may not be seen in cell types other than macrophages, caution will now be needed in interpreting all results in which 15d-PGJ2 or the thiazolidinediones are used as putative PPAR{gamma}-specific ligands.


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OVERALL CONCLUSIONS
 
It is clear that PPAR{alpha} and PPAR{gamma} likely play a role in inflammatory and immune responses. However, the specific role played by PPAR{gamma} has become less clear recently as a result of our new understanding of the lack of PPAR{gamma} specificity of 15d-PGJ2 and perhaps the thiazolidinediones as well. Given the recent studies with PPAR{gamma} null macrophages, this issue may be especially relevant in studies of macrophage function in inflammation and immunity. The clarification of this issue may depend on the identification and use of truly PPAR{gamma}-specific ligands. In addition, the identification of endogenous ligands for PPAR{gamma} in different cell types remains an important area of investigation. Future studies involving monocyte/macrophages should also examine the relevance of PPARs in antigen presentation. In addition, it will be crucial to further characterize the function of PPAR{gamma} in dendritic cells—cells that play a pivotal role in regulating the adaptive immune response.

The studies of PPAR{gamma} in T cells have opened up yet another possible role for PPAR{gamma} in the regulation of inflammation and immunity and more specifically in the regulation of adaptive immunity. In the future, it will be interesting to determine whether PPAR{gamma} ligands have differential effects on T-cell subsets. An example of this might include a differential effect of PPAR{gamma} ligands on Th1 versus Th2 cells and thus an involvement in immune deviation. Also, as pointed out by Harris and Phipps [88 ], investigations into a possible role of PPAR{gamma} in the regulation of T-cell development could prove enlightening. Unfortunately, the T-cell studies to date have also used ligands that now have been identified, at least in macrophages, as having physiological effects that are PPAR{gamma}-independent. Definitive studies regarding the role of PPAR{gamma} in murine T-cell-related inflammation and immunity will likely await the development of the relevant T-cell-specific (and perhaps conditional) knockout mice. Alternatively, the demonstration of PPAR{gamma} specificity of thiazolidinediones in T-cell function or the identification of new PPAR{gamma}-specific ligands could also clarify the role of PPAR{gamma} in T-cell function. Even with these caveats, it should be noted that the thiazolidinediones (pioglitazone and rosiglitazone) are being used clinically in humans for the treatment of type-2 diabetes. The inflammatory and immune responses of the patients taking these medications could be studied and could be used to document the effects of these ligands (PPAR{gamma}-dependent or -independent) on inflammation and immunity in vivo in humans. In addition, Barroso et al. [103 ] have identified a small number of patients with mutations in the ligand-binding domains of PPAR{gamma}. These patients manifest a clinical syndrome including severe insulin resistance, diabetes, and hypertension. Such patients could represent an important resource for studying the role of PPAR{gamma} in inflammation and the immune response.

Finally, a role for PPAR{gamma} has been demonstrated recently in normal murine B cells and B-cell lines [104 ]. In this study, PPAR{gamma} ligands were shown to induce apoptosis in these cells. Future studies will be needed to address the effects of PPAR{gamma} ligands on the normal B-cell immune response, including antibody production. The role of PPAR{gamma} in the regulation of inflammation and the immune response and the possible therapeutic role for PPAR{gamma} ligands in the treatment of diseases involving aberrant inflammatory/immune responses still remain unresolved issues with potentially significant theoretical and practical importance.

Received August 16, 2001; revised November 30, 2001; accepted December 3, 2001.


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