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PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-γ IS A NEW THERAPEUTIC TARGET IN SEPSIS AND INFLAMMATION

Zingarelli, Basilia*; Cook, James A

doi: 10.1097/01.shk.0000160521.91363.88
Review Article
Free

Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. PPARγ forms a heterodimer with the retinoid X receptor and upon ligand-activation binds to the PPAR response element in the promoter of genes to allow transcription. The class of insulin-sensitizing drugs known as thiazolidinediones have been identified as specific PPARγ agonists that have allowed the characterization of many genes regulated by PPARγ. Thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone. In addition to these synthetic agonists, cyclopentenone prostaglandins of the J2 series have been identified as natural ligands for PPARγ. Several in vitro and in vivo studies have demonstrated that pharmacological activation of PPARγ by 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) or thiazolidinediones has anti-inflammatory effects. This article provides an overview of the role of PPARγ in regulating the inflammatory response and emphasizes the potential efficacy of PPARγ ligands as novel therapeutic approaches beyond diabetes in sepsis, inflammation, and reperfusion injury.

*Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and the College of Medicine, University of Cincinnati, Cincinnati, Ohio; and †Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina

Received 31 Jan 2005; first review completed 9 Feb 2005; accepted in final form 15 Feb 2005

Address reprint requests to Basilia Zingarelli, MD, PhD, Cincinnati Children's Hospital Medical Center, Division of Critical Care Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: basilia.zingarelli@cchmc.org.

Financial support was provided by the National Institutes of Health (grants R01 GM-67202 and R01 HL-60730 to B.Z. and grant R01 GM-27673 to J.A.C.).

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PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS)

PPARs represent an important pathway that likely influences cellular response by altering gene expression. PPARs are a large superfamily of nuclear receptors for steroid, thyroid, and retinoid hormones that require ligand binding (1). Unlike plasma membrane receptors that signal through second messengers, nuclear receptors can function directly as transcription factors to control gene regulation. Although most of the research that has been published on PPARs focuses on the role of the nuclear receptors on energy metabolism in adipose tissue, PPARs have also been shown to be expressed in vascular smooth muscle cells, endothelial cells, monocytes, and macrophages (2, 3). Three isoforms of the PPAR subfamily have been identified in mammals: PPARα, PPARβ/δ, and PPARγ (4). PPARβ/δ is the most widely expressed isotype and low levels are found in almost all tissues examined (3); however, its role has not been fully identified. It has been demonstrated that PPARβ/δ regulates cholesterol metabolism in insulin-deficient mice (5), functions as a thermogenic transcription factor for the induction of genes for fatty acid oxidation and energy dissipation (6), and is involved in blastocyst implantation (7). More extensive research has been conducted on PPARα and PPARγ. PPARα is involved in the stimulation of lipid oxidation, lipoprotein metabolism, and inhibition of vascular inflammation, such as atherosclerosis (8).

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THE PPARγ MEMBER

PPARγ is important in the regulation of adipocyte proliferation, glucose homeostasis, acceleration of leukotriene degradation, cell cycle control, carcinogenesis, atherosclerosis, and inflammation (9). In humans, four isoforms of PPARγ mRNA have been identified (9, 10). PPARγ1, PPARγ3, and PPARγ4 mRNA give rise to the identical gene product PPARγ 1. PPARγ2 mRNA gives rise to the PPARγ2 protein, which is 28 amino acids longer at the NH2 terminus. The fact that four isoforms exist for PPARγ mRNA suggests tissue-specific expression patterns. PPARγ 1 is expressed to varying degrees in all tissues (9), whereas PPARγ2 is expressed in adipose tissue (11). PPARγ3 is found in adipose tissue, colon, and in the macrophages and T lymphocytes (12, 13). There are currently no studies on the distribution of PPARγ4 (10).

The PPARγ protein can be divided into four distinct domains for functionality. The N-terminal domain is designated the activation domain (A/B domain) or activation function-1 (AF-1) (14). Phosphorylation of this domain at serine residue 82 leads to inhibition of PPARγ transactivation (15, 16). The domain C component of PPARγ interacts with promoter regions of responsive target genes (17). The hinge domain (D) is next, which confers flexibility of the protein for the DNA- and ligand-binding domains. The carboxyl terminus designated the E/F region or activation function-2 (AF-2) domain is responsible for binding of ligands and for heterodimerization (Fig. 1).

Fig. 1

Fig. 1

PPARγ and other members of the nuclear receptor superfamily are characterized by the necessity for ligand binding before activation. Once activated by ligand, PPARγ forms a heterodimer with the retinoic acid receptor (RXR). The interaction with the RXR allows the recruitment of a set of cofactors and the binding of the heterodimer to the PPAR response element (PPRE) in the promoter region of certain target genes, thus modulating transcription (17-19) (Fig. 2). PPARγ can directly activate transcription of specific genes, e.g., CD36 (20). However, it can also transrepress certain genes in a DNA-binding-independent manner. The latter effect may be particularly important in inhibiting proinflammatory gene expression. Three potential mechanisms of transrepression have been implicated. One mechanism involves the binding of activated PPARγ-RXR heterodimers to coactivators that are essential for all transcription factors that induce proinflammatory gene expression (21). The transcription factors include activator protein-1 (AP-1), nuclear factor-κB (NF-κB), signal transducer and activation of transcription (STAT), and nuclear factor of activated T cells (NFAT). Coactivators include coactivators of CREB-binding protein (CBP) and p-300, which are bound by PPARγ (22). The second mechanism whereby PPARγ-RXR complexes transrepress gene expression is through direct binding to transcription factors. This has been shown to occur with the NFAT in T cells (23) and the NF-κB subunits p50 and p65 (24). The third mechanism whereby PPARγ may transrepress gene expression is through inhibition of mitogen-activated protein (MAP) kinases. Phosphorylation of c-Jun amino-terminal kinase (JNK) and p-38 have been shown to be diminished in heterozygous PPARγ-deficient (PPARγ+/−) mice in response to specific stimuli (25) (Fig. 3).

Fig. 2

Fig. 2

Fig. 3

Fig. 3

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Ligands for PPARγ: thiazolidinediones and cyclopentenone prostaglandins

The class of insulin-sensitizing drugs known as thiazolidinediones have been identified as specific PPARγ agonists that have allowed the characterization of many genes regulated by PPARγ (18, 19). Despite an initial lack of understanding of a physiological mode of action, thiazolidinediones have been studied in clinical trials to treat diabetic insulin resistance (26). Studies involving the effects of thiazolidinediones in cell-based assays led to the discovery that thiazolidinediones can promote adipocyte differentiation by activating PPARγ (27, 28). Thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone (29). Although many synthetic PPARγ agonists have been identified, the natural ligands for PPARγ are unknown. Studies demonstrating that arachidonic acid can activate PPARγ (30, 31) led to speculation that an endogenous arachidonic acid metabolite may be the natural PPARγ agonist. Transfection studies have shown that PGD2, PGJ2, 12-PGJ2, and 15d-PGJ2 activate PPARγ with EC50 in the range of 1 to 5 μM, whereas PGG2, PGF2, PGH2, PGE2, and PGI2 do not activate PPARγ-dependent reporter genes (1). Kliewer et al. (32) demonstrated that PGD2 activated PPARγ-dependent transcription but it did not bind to PPARγ, whereas the PGJ2 metabolites were able to bind the receptor. The data suggested that PGD2 might activate PPARγ through a pathway that involves metabolism of PGD2 to the PGJ2 eicosanoids. It has been shown that PGD2 undergoes spontaneous dehydration in the cyclopentane ring to form PGJ2 (Fig. 4). Further dehydration leads to the production of Δ12-PGJ2 and finally to 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). PGD2 and 12-PGJ2 have been measured in human and monkey urine (33, 34). Recently, interest in the anti-inflammatory effects of the PGJ2 family of eicosanoids has grown enormously as a result of two independent studies (30, 31). The studies demonstrated that PGJ2 metabolites inhibited nitric oxide (NO) and cytokine production in immunostimulated macrophages. As these eicosanoids have no known plasma membrane receptors, these inhibitory effects seem to be mediated by a specific interaction with the nuclear PPARγ.

Fig. 4

Fig. 4

Members of the 12/15-lipoxygenase family of eicosanoids, including 15-hydroxy-eicosatetraeonic acid (15-HETE) and 13-hydroxyoctadecadienoic acid (13-HODE), have also been identified as PPARγ agonists (35, 36). Nonsteroidal anti-inflammatory drugs, which inhibit cyclo-oxygenase-1 (COX-1) and COX-2 (37), such as ibuprofen, indomethacin, flufenamic acid, and fenoprofen, have also been identified as PPARγ agonists. These drugs bind to PPARγ and activate PPARγ-dependent transcription, but at much higher concentrations compared with other PPARγ agonists (38).

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Differential effects of PPARγ on the inflammatory response in myeloid cells

It has been proposed that PPARγ plays a crucial role in the control of the inflammatory response. For example, the PPARγ ligands 15d-PGJ2 and rosiglitazone are potent anti-inflammatory agents that repress the expression of several inflammatory response genes in activated macrophages, including the genes encoding the inducible NO synthase (iNOS), tumor necrosis factor-α (TNFα), gelatinase B, and inducible COX-2 (30, 31). Similarly, 15d-PGJ2 and troglitazone, another synthetic PPARγ agonist, inhibited production of TNFα, interleukin (IL)-6, and IL-1β in human monocytes stimulated with phorbol myristyl acid (31). Ricote et al. (31) also demonstrated that the inhibitory effects of 15-PGJ2 and rosiglitazone resulted from the inability of transcription factors AP-1, STAT, and NF-κB to bind to the iNOS promoter in monocytes. Other investigations have demonstrated that 15d-PGJ2 and 13-HODE reduced LPS-stimulated monocyte production of IL-10 and IL-12 (39). These anti-inflammatory actions of PPARγ ligands can be shown to microbial stimuli in addition to endotoxin. We investigated the effect of 15d-PGJ2 and the thiazolidinedione troglitazone on heat-killed Staphylococcus aureus, a Toll-like receptor (TLR)-2 ligand, and Escherichia coli, a TLR4 ligand, on thromboxane 2 (TxB2) and NO production by rat peritoneal macrophages (40). 15d-PGJ2 and troglitazone dose dependently suppressed TxB2, whereas only 15d-PGJ2 suppressed NO production. These studies demonstrate that 15d-PGJ2 and thiazolidinediones exert differential effects on TLR-induced inflammatory responses. In addition to peritoneal macrophages and peripheral blood monocytes, PPARγ ligands have been shown to suppress Kupffer cell and alveolar macrophage inflammatory responses. The thiazolidinedione pioglitazone suppressed TNFα production in rat Kupffer cells and the latter inhibition was potentiated with RXR agonists (41). In human alveolar macrophages, troglitazone suppressed LPS-induced TNFα but augmented CD36 expression. In addition to macrophages, PPARγ is also expressed in CD4 and CD8 T cells. Importantly, it has been shown that T cell PPARγ may indirectly modulate macrophage activation by repressing interferon (IFN)γ promoter sites and IFNγ production through interference with c-Jun activation (42).

In addition to anti-inflammatory effects, PPARγ ligands have been shown to induce certain proinflammatory responses. The latter include upregulation of the macrophage proinflammatory surface receptors (CD14, CD11/CD18, CD36, and scavenger receptor B1) (43-45). Nevertheless, it appears that upregulation of CD36 still may function in an anti-inflammatory manner through promoting phagocytosis of apoptotic neutrophils by tethering the cells to macrophages before engulfment (46). Other examples of the complexity of the pro- and anti-inflammatory PPARγ functions have been observed in human monocytic cell lines where 15d-PGJ2 induced expression of IL-8, but suppressed expression of monocyte chemoattractant protein-1 (47). Interestingly, rosiglitazone had no effect on LPS-induced IL-8, but suppressed matrix metalloproteinase-9 (48). Therefore, the effect of PPARγ ligands on the inflammatory response appears to be complex and dependent upon the specific PPARγ ligand used, the mode of macrophage/monocyte activation, and the mediators that are measured.

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Differential expression of PPARγ in inflammation

Other in vitro studies support a role for PPARγ in inflammation as PPARγ expression appears to be altered by proinflammatory mediators. It has been shown that expression of PPARγ is low in monocytes and increases as monocytes differentiate into macrophages (31, 43). PPARγ agonists induced macrophage differentiation and increased the expression of the cell surface markers CD11/18, CD14, and CD36 in monocytes (43). In adipose tissue, PPARγ mRNA and protein expression decreased after mice were challenged in vivo with LPS (49). In other studies, inflammatory cytokines, including TNFα, IL-1β, and IL-6, also decreased PPARγ expression in adipose tissue. The suppression of PPARγ mRNA expression caused by the cytokines was reversed by treatment with troglitazone and pioglitazone (50).

More recently, hearts from mice treated with LPS were examined for altered expression of PPARγ and coactivators (51). LPS-treated mice exhibited reduced expression of all isoforms of PPARγ and RXRα and thyroid receptor (TR). Additionally, the coactivators CBP/P300, steroid coactivator (SRC-1) and SRC-3, TR-associated protein 220 and PPARγ coactivator (PGG-1) were reduced. Because the nuclear receptors, cofactors, and the genes that they regulate are important in myocardial fatty acid oxidation, reduced expression of these factors may contribute to altered myocardial fatty acid metabolism and contractility in endotoxic shock (51). We have also demonstrated that the cardiovascular hypodynamic phase of septic shock is associated with down-regulation of PPARγ expression on the endothelium of thoracic aortas and in the bronchial epithelium in rats (52). PPARγ protein levels were also decreased in whole colonic tissue, lamina propria lymphocytes, and peritoneal exudate cells during the course of experimental colitis in mice (53).

In contrast to other tissues, inflammatory stimuli appear to increase PPARγ expression in immune cells. Studies by Leininger et al. (54) demonstrate that in porcine white blood cells, PPARγ protein expression increased 2-fold over basal in response to acute endotoxemia. These studies suggest that LPS regulates PPARγ expression differently in various cell types. In nonactivated murine monocytes/macrophages, PPARγ is expressed at low levels. However, the level of PPARγ expression increases in activated peritoneal macrophages (55). Similar responses are seen with PPARγ expression in peripheral blood monocytes. IL-4 also strongly induces PPARγ expression in murine peritoneal macrophages and peripheral blood monocytes (36). Collectively, these studies suggest that during inflammatory processes, PPARγ expression may be differently modulated and may be dependent on several variables, including cell types, inflammatory challenge, and involvement of other signaling pathways.

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Anti-inflammatory feedback loops involving PPARγ ligands

The anti-inflammatory properties of PPARγ ligands may also involve negative feedback control on proinflammatory pathways. For example, in in vitro studies with fetal hepatocytes, upon inhibition of COX with indomethacin or the COX-2 inhibitor NS398, LPS induced a 5-fold greater increase in COX-2 protein than control. This effect was related to the absence of feedback from 15d-PGJ2 (56). Inoue et al. (57) showed that 15d-PGJ2 suppresses COX-2 in macrophage-like cells by interfering with the NF-κB signaling pathway, thus suggesting that expression of COX-2 is regulated by a negative feedback loop mediated through PPARγ. Similarly to this finding, it has been shown that the PPARγ ligands, 15d-PGJ2 and troglitazone, can inhibit the growth of synoviocytes from patients with rheumatoid arthritis in vitro and can suppress the chronic inflammation of adjuvant-induced arthritis in rats. The anti-inflammatory properties of 15d-PGJ2 were linked to suppression of cytosolic phospholipase A2 and COX-2 (58). This physiological negative feedback regulator of prostaglandin synthesis and inflammatory response has also been demonstrated in in vivo studies. It has been shown that in carrageenan-induced pleurisy in rats there was an early induction of COX-2 that coincided with synthesis of PGE2. By contrast, PGD2 and 15-PGJ2 production declined as inflammation increased. However, at 48 h there is a second induction of COX-2 with minimal PGE2 synthesis but with increased PGD2 and 15-PGJ2. COX-2 inhibitors attenuated the early inflammation, but augmented the inflammation in response to the delayed COX-2 expression. The latter effect was reversed by replacement of PGD2 and 15-PGJ2 (59). However, the notion that endogenous 15d-PGJ2 is implicated in the resolution of inflammation has been challenged by a recent study demonstrating that endogenous 15d-PGJ2 was not increased after induction of COX-2 in preadipocytes. It was also demonstrated that urinary excretion of 15d-PGJ2 was not increased after LPS administration in human volunteers even though there was an increase in urinary excretion of a PGI2 metabolite (60). Despite the controversy over physiologic endogenous ligands for PPARγ, this negative feedback loop involving 15d-PGJ2 and PPARγ has also been linked to macrophage desensitization, a phenomenon known as LPS tolerance. Suppression of cell signaling and mediator production, which occurs in LPS tolerance, was blocked by inhibition of PPARγ function (61).

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PPARγ-independent effects of PPARγ ligands

Several studies have demonstrated that synthetic and natural PPARγ ligands have PPARγ-independent effects (Fig. 3). Santoro (62) demonstrated that PGJ2 and 15d-PGJ2 inhibit oxidant-induced NF-κB translocation to the nucleus through inhibition of IκBα phosphorylation. Petrova et al. (37) demonstrated that although 15d-PGJ2 inhibited NF-κB transcriptional activity and inhibited iNOS mRNA and NO production in microglial cells, the PPARγ agonist troglitazone had no effect. Similarly, 15d-PGJ2 has been shown to inhibit β2-integrin-dependent oxidative burst in neutrophils, whereas synthetic PPARγ agonists had no effect (63). In another study, Thieringer et al. (64) demonstrated that only 15d-PGJ2 out of five PPARγ agonists examined inhibited LPS-induced TNFα and IL-6 production in vitro and in vivo over a wide range of concentrations. Overexpression of a dominant-negative PPARγ mutant or treatment with a PPARγ antagonist failed to attenuate the inhibitory actions of 15d-PGJ2 on cytokine signaling in pancreatic β cells (65).

The NF-κB pathway appears to be a target for PPARγ-independent effects of cyclopentenone prostaglandins. Studies by Straus et al. (66) demonstrate that 15d-PGJ2 inhibited LPS-induced degradation of inhibitor-κBα (IκBα) and NF-κB gene activation by covalent modification of critical cysteine residues of the inhibitor-κB kinase (IKK) and the DNA-binding domain of the p65 NF-κB subunit. Castrillo et al. (67) compared the effect of a thiazolidinedione-unrelated PPARγ agonist to 15d-PGJ2 and thiazolidinediones. The thiazolidinedione-unrelated compound and 15d-PGJ2 were able to modify cysteine residues of IKK and to inhibit activation of NF-κB in cells deficient in PPARγ. More recently, 15d-PGJ2 has been demonstrated to covalently modify cysteine 62 of NF-κB subunit p50 and to reduce recombinant DNA binding in a dose-dependent manner (68). Studies from our laboratory have shown that 15d-PGJ2 may affect signaling to extracellular-regulated kinase (ERK) 1 and 2, and induce IκBα synthesis (40).

The PPARγ-independent reactivity of 15d-PGJ2 has been attributed to its cyclopentenone ring that contains an electrophilic carbon that can react with nucleophiles such as free sulfhydryls of glutathione and cysteine residues (31). As with IKK, ERK 1/2 also possess critical cysteine residues. This may represent a mechanism whereby 15d-PGJ2 inhibits ERK 1/2 activity. This is further substantiated by our finding that the cyclopentenone ring 2-cyclopenten-1-one inhibited LPS-induced activation of ERK 1/2 (albeit less potently than 15d-PGJ2) (69). Further evidence supporting independent effects of PPARγ ligands has been derived from PPARγ-null-deficient macrophages in chimeric mice that were generated by injection of embryonic stem cells into wild-type blastocysts. Although expression of CD36 was PPARγ dependent, there was no difference in expression of CD14, TNFα, and IL-6 after LPS stimulation (20, 70).

Recently, it has been shown that PPARγ ligands may induce expression of heat shock proteins (HSP), which are known to have broad cytoprotective properties (71). For example, the PGJ2 family stimulates the heat shock response in K562 erythroleukemia cells (72). The ability of 15d-PGJ2 and troglitazone to block cytokine-induced iNOS in macrophages and IL-1-induced IκBα degradation and JNK phosphorylation in islet cells were associated with expression of HSP70 (73). Similarly, Ianaro et al. (74) have reported that in vivo treatment with 15d-PGJ2, its precursor PGD2, and the cyclopentenone ring induced HSF1 activation and HSP72 expression in inflamed tissue and that this effect was associated with the remission of the inflammatory reaction. One mechanism whereby HSPs may regulate inflammation is by altered activation of NF-κB through increased cytoplasmic binding to IκBα. Rossi et al. (75) demonstrated for the first time that induction of the stress response with cyclopentenone prostaglandins inhibited IκBα degradation. Thus, induction of the heat shock response may represent an important anti-inflammatory mechanism of cyclopentenone prostaglandins and PPARγ ligands.

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In vivo anti-inflammatory effects of PPARγ ligands

The possibility that PPARγ has a modulatory role in the inflammatory response has prompted a number of groups to carry out in vivo studies to assess the potential use of thiazolidinediones and cyclopentenone prostaglandins as anti-inflammatory drugs. For example, intraperitoneal administration of the PPARγ ligands 15d-PGJ2 and troglitazone ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in rats (76). The anti-inflammatory activity of thiazolidinediones against adjuvant-induced arthritis in mice was secondary to the inhibition of NF-κB pathway (77). We have also demonstrated that pharmacological activation of PPARγ by several ligands ameliorates the pathophysiologic changes of cardiovascular shock secondary to polymicrobial sepsis. Specifically, PPARγ ligands ameliorated the hemodynamic profile, reduced neutrophil infiltration in lung, colon, and liver, and reduced cytokine production. These beneficial effects of PPARγ ligands were associated with inhibition of the activity of IKK and JNK, and inhibition of the subsequent activation of NF-κB and AP-1 in the lung (52). Furthermore, we have demonstrated that 15d-PGJ2 reduces expression of adhesion molecules and tissue leukosequestration through inhibition of the NF-κB pathway during endotoxic shock in the rat (78). Similarly, Collin et al. (79) confirmed that 15d-PGJ2 reduced the multiple organ injury and dysfunction caused by endotoxin. Recently, a role of PPARγ has also been proposed in the pathophysiology of myocardial ischemia and reperfusion (80). In nondiabetic pigs, chronic treatment with troglitazone improved recovery of left ventricular systolic and diastolic function and substrate metabolism after acute ischemia (81). Similarly, in isolated heart from normal or diabetic rats, rosiglitazone improved postischemic functional recovery. This cardioprotective effect was associated with inhibition of JNK phosphorylation and AP-1 activation (82). Pioglitazone improved left ventricular remodeling and function, and attenuated cardiac expression of inflammatory cytokines and chemokines in mice and rats with postischemia heart failure (83, 84). Several other PPARγ ligands have been shown to reduce infarct size in rats subjected to myocardial ischemia and reperfusion (85). We have also demonstrated that the cyclopentenone prostaglandin 15d-PGJ2 affords cardioprotection in rats subjected to coronary occlusion and reperfusion, and this beneficial effect is associated with induction of the heat shock response (86). Similar beneficial effects of PPARγ ligands have been reported in other experimental models of gut (87), and renal ischemia and reperfusion injury (88), and in hemorrhagic shock (89). Using a murine model of inflammatory bowel disease, Su et al. (90) have demonstrated that treatment with thiazolidinediones attenuated intestinal inflammation by inhibiting the activation of NF-κB via an IκBα-dependent mechanism. Similarly, PPARγ gene delivery using adenovirus-PPARγ enhanced the anti-inflammatory response of a PPARγ ligand, resulting in marked amelioration of tissue inflammation associated with colitis, such as attenuation of intercellular adhesion molecule-1 (ICAM-1), COX-2, and TNF-α expression (53). An open-label trial with rosiglitazone in patients with ulcerative colitis confirmed the possibility that PPARγ ligands may have therapeutic potentials in inflammatory bowel diseases (91).

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CONCLUSION

The recent demonstration that cyclopentenone prostaglandins and thiazolidinedione compounds exhibit potent anti-inflammatory properties has sparked renewed interest in the nuclear receptor PPARγ as a major regulator of inflammation. In the future, large clinical studies for off-label uses with the currently used thiazolidinediones should allow determination as to whether these drugs may have a wider range of therapeutic application beyond diabetes. Yet another area that needs to be investigated is the possibility of PPARγ-independent anti-inflammatory effects of the putative natural occurring and synthetic ligands. Understanding the molecular mechanisms of PPARγ ligands by the use of gene targeting technology should clarify this issue and may expand our knowledge of their biological actions and their potential use in therapies that target inflammation.

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REFERENCES

1. Moore KJ, Fitzgerald ML, Freeman MW: Peroxisome proliferator-activated receptors in macrophage biology: friend or foe? Curr Opin Lipidol 12:519-527, 2001.
2. Bishop-Bailey D: Peroxisome proliferator-activated receptors in the cardiovascular system. Br J Pharmacol 129:823-834, 2000.
3. Guan Y, Zhang Y, Breyer MD: The role of PPARs in the transcriptional control of cellular processes. Drug News Perspect 15:147-154, 2002.
4. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P: The nuclear receptor superfamily: the second decade. Cell 83:835-839, 1995.
5. Leibowitz MD, Fievet C, Hennuyer N, Peinado-Onsurbe J, Duez H, Bergera J, Cullinan CA, Sparrow CP, Baffic J, Berger GD, Santini C, Marquis RW, Tolman RL, Smith RG, Moller DE, Auwerx J: Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Lett 473:333-336, 2000.
6. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM: Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113:159-170, 2003.
7. Lim H, Gupta RA, Ma WG, Paria BC, Moller DE, Morrow JD, DuBois RN, Trzaskos JM, Dey SK: Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARδ. Genes Dev 13:1561-1574, 1999.
8. Fruchart JC, Duriez P, Staels B: Peroxisome proliferator-activated receptor-α activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin Lipidol 10:245-257, 1999.
9. Rocchi S, Auwerx J: Peroxisome proliferator-activated receptor-γ: a versatile metabolic regulator. Ann Med 31:342-351, 1999.
10. Sundvold H, Lien S: Identification of a novel peroxisome proliferator-activated receptor (PPAR)γ promoter in man and transactivation by the nuclear receptor RORα1. Biochem Biophys Res Commun 287:383-390, 2001.
11. Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM: C/EBPα induces adipogenesis through PPARγ: a unified pathway. Genes Dev 16:22-26, 2002.
12. Fajas L, Fruchart JC, Auwerx J: PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter. FEBS Lett 438:55-60, 1998.
13. Tautenhahn A, Brune B, von Knethen A: Activation-induced PPARγ expression sensitizes primary human T cells toward apoptosis. J Leukocyte Biol 73:665-672, 2003.
14. Werman A, Hollenberg A, Solanes G, Bjorbaek C, Vidal-Puig AJ, Flier JS: Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor γ (PPARγ). Differential activity of PPARγ1 and -2 isoforms and influence of insulin. J Biol Chem 272:20230-20235, 1997.
15. Han J, Hajjar DP, Tauras JM, Feng J, Gotto AM Jr, Nicholson AC: Transforming growth factor-β1 (TGF-β1) and TGF-β2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-γ. J Biol Chem 275:1241-1246, 2000.
16. Hsi LC, Wilson L, Nixon J, Eling TE: 15-Lipoxygenase-1 metabolites down-regulate peroxisome proliferator-activated receptor γ via the MAPK signaling pathway. J Biol Chem 276:34545-34552, 2001.
17. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV: Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature 395:137-143, 1998.
18. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM: Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358:771-774, 1992.
19. Palmer CN, Hsu MH, Griffin HJ, Johnson EF: Novel sequence determinants in peroxisome proliferator signaling. J Biol Chem 270:16114-16121, 1995.
20. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM: PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7:48-52, 2001.
21. Holloway AF, Rao S, Shannon MF: Regulation of cytokine gene transcription in the immune system. Mol Immunol 38:567-580, 2002.
22. Li M, Pascual G, Glass CK: Peroxisome proliferator-activated receptor γ-dependent repression of the inducible nitric oxide synthase gene. Mol Cell Biol 20:4699-4707, 2000.
23. Yang XY, Wang LH, Chen T, Hodge DR, Resau JH, DaSilva L, Farrar WL: Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor γ (PPARγ) agonists. PPARγ co-association with transcription factor NFAT. J Biol Chem 275:4541-4544, 2000.
24. Chung SW, Kang BY, Kim SH, Pak YK, Cho D, Trinchieri G, Kim TS: Oxidized low-density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-γ and nuclear factor-κB. J Biol Chem 275:32681-32687, 2000.
25. Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P, Leibowitz MD, Colombel JF, Auwerx J: Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor γ (PPARγ) heterodimer. A basis for new therapeutic strategies. J Exp Med 193:827-838, 2001.
26. Hulin B: New hypoglycaemic agents. Prog Med Chem 31:1-58, 1994.
27. Hiragun A, Sato M, Mitsui H: Preadipocyte differentiation in vitro: identification of a highly active adipogenic agent. J Cell Physiol 134:124-130, 1988.
28. Kletzien RF, Clarke SD, Ulrich RG: Enhancement of adipocyte differentiation by an insulin-sensitizing agent. Mol Pharmacol 41:393-398, 1992.
29. Willson TM, Lehmann JM, Kliewer SA: Discovery of ligands for the nuclear peroxisome proliferator-activated receptors. Ann N Y Acad Sci 804:276-283, 1996.
30. Jiang C, Ting AT, Seed B: PPARγ agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82-86, 1998.
31. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK: The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391:79-82, 1998.
32. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM: A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 83:813-819, 1995.
33. Fitzpatrick FA, Wynalda MA: Albumin-catalyzed metabolism of prostaglandin D2. Identification of products formed in vitro. J Biol Chem 258:11713-11718, 1983.
34. Hirata Y, Hayashi H, Ito S, Kikawa Y, Ishibashi M, Sudo M, Miyazaki H, Fukushima M, Narumiya S, Hayaishi O: Occurrence of 9-deoxy-δ 9,δ 12-13,14-dihydroprostaglandin D2 in human urine. J Biol Chem 263:16619-16625, 1988.
35. Conrad DJ, Kuhn H, Mulkins M, Highland E, Sigal E: Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci USA 89:217-221, 1992.
36. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK: Interleukin-4-dependent production of PPARγ ligands in macrophages by 12/15-lipoxygenase. Nature 400:378-382, 1999.
37. Petrova TV, Akama KT, Van Eldik LJ: Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Δ12,14-prostaglandin J2. Proc Natl Acad Sci USA 96:4668-4673, 1999.
38. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 272:3406-3410, 1997.
39. Azuma Y, Shinohara M, Wang PL, Ohura K: 15-Deoxy-Δ12,14-prostaglandin J2 inhibits IL-10 and IL-12 production by macrophages. Biochem Biophys Res Commun 283:344-346, 2001.
40. Guyton K, Zingarelli B, Tempel GE, Reilly C, Gilkeson G, Halushka PV, Cook JA: Peroxisome proliferator-activated receptor-γ agonists modulate macrophage activation by gram-negative and gram-positive bacterial stimuli. Shock 20:56-60, 2003.
41. Uchimura K, Nakamuta M, Enjoji M, Irie T, Sugimoto R, Muta T, Iwamoto H, Nawata H: Activation of retinoic X receptor and peroxisome proliferator-activated receptor-γ inhibits nitric oxide and tumor necrosis factor-α production in rat Kupffer cells. Hepatology 33:91-99, 2001.
42. Cunard R, Eto Y, Muljadi JT, Glass CK, Kelly CJ, Ricote M: Repression of IFN-γ expression by peroxisome proliferator-activated receptor γ. J Immunol 172:7530-7536, 2004.
43. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM: PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241-252, 1998.
44. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM: Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 93:229-240, 1998.
45. Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J, Fruchart JC, Tedgui A, Najib-Fruchart J, Staels B: CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 101:2411-2417, 2000.
46. Hoffmann PR, deCathelineau AM, Ogden CA, Leverrier Y, Bratton DL, Daleke DL, Ridley AJ, Fadok VA, Henson PM: Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155:649-659, 2001.
47. Zhang X, Wang JM, Gong WH, Mukaida N, Young HA: Differential regulation of chemokine gene expression by 15-deoxy-Δ12,14 prostaglandin J2. J Immunol 166:7104-7111, 2001.
48. Shu H, Wong B, Zhou G, Li Y, Berger J, Woods JW, Wright SD, Cai TQ: Activation of PPARα or γ reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells. Biochem Biophys Res Commun 267:345-349, 2000.
49. Hill MR, Young MD, McCurdy CM, Gimble JM: Decreased expression of murine PPARγ in adipose tissue during endotoxemia. Endocrinology 138:3073-3076, 1997.
50. Tanaka T, Itoh H, Doi K, Fukunaga Y, Hosoda K, Shintani M, Yamashita J, Chun TH, Inoue M, Masatsugu K, Sawada N, Saito T, Inoue G, Nishimura H, Yoshimasa Y, Nakao K: Down regulation of peroxisome proliferator-activated receptor-γ expression by inflammatory cytokines and its reversal by thiazolidinediones. Diabetologia 42:702-710, 1999.
51. Feingold K, Kim MS, Shigenaga J, Moser A, Grunfeld C: Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab 286:E201-E207, 2004.
52. Zingarelli B, Sheehan M, Hake PW, O'Connor M, Denenberg A, Cook JA: Peroxisome proliferator activator receptor-γ ligands, 15-deoxy-Δ12,14-PGJ2 and ciglitazone, reduces systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways. J Immunol 171:6827-6837, 2003.
53. Katayama K, Wada K, Nakajima A, Mizuguchi H, Hayakawa T, Nakagawa S, Kadowaki T, Nagai R, Kamisaki Y, Blumberg RS, Mayumi T: A novel PPARγ gene therapy to control inflammation associated with inflammatory bowel disease in a murine model. Gastroenterology 124:1315-1324, 2003.
54. Leininger MT, Portocarrero CP, Houseknecht KL: Peroxisome proliferator-activated receptor γ 1 expression in porcine white blood cells: dynamic regulation with acute endotoxemia. Biochem Biophys Res Commun 263:749-753, 1999.
55. Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W, Glass CK: Expression of the peroxisome proliferator-activated receptor γ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 95:7614-7619, 1998.
56. Callejas NA, Castrillo A, Bosca L, Martin-Sanz P: Inhibition of prostaglandin synthesis up-regulates cyclooxygenase-2 induced by lipopolysaccharide and peroxisomal proliferators. J Pharmacol Exp Ther 288:1235-1241, 1999.
57. Inoue H, Tanabe T, Umesono K: Feedback control of cyclooxygenase-2 expression through PPARγ. J Biol Chem 275:28028-28032, 2000.
58. Tsubouchi Y, Kawahito Y, Kohno M, Inoue K, Hla T, Sano H: Feedback control of the arachidonate cascade in rheumatoid synoviocytes by 15-deoxy-Δ12,14-prostaglandin J2. Biochem Biophys Res Commun 283:750-755, 2001.
59. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA: Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 5:698-701, 1999.
60. Bell-Parikh LC, Ide T, Lawson JA, McNamara P, Reilly M, FitzGerald GA: Biosynthesis of 15-deoxy-Δ12,14-PGJ2 and the ligation of PPARγ. J Clin Invest 112:945-955, 2003.
61. Von Knethen AA, Brune B: Delayed activation of PPARγ by LPS and IFN-γ attenuates the oxidative burst in macrophages. FASEB J 15:535-544, 2001.
62. Santoro MG: Antiviral activity of cyclopentenone prostanoids. Trends Microbiol 5:276-281, 1997.
63. Vaidya S, Somers EP, Wright SD, Detmers PA, Bansal VS: 15-Deoxy-Δ12,14 prostaglandin J2 inhibits the β2 integrin-dependent oxidative burst: involvement of a mechanism distinct from peroxisome proliferator-activated receptor γ ligation. J Immunol 163:6187-6192, 1999.
64. Thieringer R, Fenyk-Melody JE, Le Grand CB, Shelton BA, Detmers PA, Somers EP, Carbin L, Moller DE, Wright SD, Berger J: Activation of peroxisome proliferator-activated receptor-γ does not inhibit IL-6 or TNFα responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol 164:1046-1054, 2000.
65. Weber SM, Scarim AL, Corbett JA: PPARγ is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic β-cells. Am J Physiol Endocrinol Metab 286:E329-E336, 2004.
66. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, Sengchanthalangsy LL, Ghosh G, Glass CK: 15-Deoxy-Δ12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc Natl Acad Sci USA 97:4844-4859, 2000.
67. Castrillo A, Mojena M, Hortelano S, Bosca L: Peroxisome proliferator-activated receptor-γ-independent inhibition of macrophage activation by the non-thiazolidinedione agonist L-796,449. Comparison with the effects of 15-deoxy-Δ12,14-prostaglandin J2. J Biol Chem 276:34082-34088, 2001.
68. Cernuda-Morollon E, Pineda-Molina E, Canada FJ, Perez-Sala D: 15-Deoxy-Δ12,14-prostaglandin J2 inhibition of NF-κB-DNA binding through covalent modification of the p50 subunit. J Biol Chem 276:35530-35536, 2001.
69. Guyton K, Bond R, Reilly C, Gilkeson G, Halushka P, Cook J: Differential effects of 15-deoxy-Δ12,14-prostaglandin J2 and a peroxisome proliferator-activated receptor γ agonist on macrophage activation. J Leukoc Biol 69:631-638, 2001.
70. Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone DS, Mortensen RM, Spiegelman BM, Freeman MW: The role of PPARγ in macrophage differentiation and cholesterol uptake. Nat Med 7:41-47, 2001.
71. Knowlton AA, Sun L: Heat-shock factor-1, steroid hormones, and regulation of heat-shock protein expression in the heart. Am J Physiol Heart Circ Physiol 280:H455-H464, 2001.
72. Amici C, Sistonen L, Santoro MG, Morimoto RI: Antiproliferative prostaglandins activate heat shock transcription factor. Proc Natl Acad Sci USA 89:6227-6231, 1992.
73. Maggi LB Jr, Sadeghi H, Weigand C, Scarim AL, Heitmeier MR, Corbett JA: Anti-inflammatory actions of 15-deoxy-Δ12,14-prostaglandin J2 and troglitazone: evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. Diabetes 49:346-355, 2000.
74. Ianaro A, Ialenti A, Maffia P, Di Meglio P, Di Rosa M, Santoro MG: Anti-inflammatory activity of 15-deoxy Δ12,14-PGJ2 and 2-cyclopenten-1-one: role of the heat shock response. Mol Pharmacol 64:85-93, 2003.
75. Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, Santoro MG: Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403:103-108, 2000.
76. Kawahito Y, Kondo M, Tsubouchi Y, Hashiramoto A, Bishop-Bailey D, Inoue K, Kohno M, Yamada R, Hla T, Sano H: 15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest 106:189-197, 2000.
77. Shiojiri T, Wada K, Nakajima A, Katayama K, Shibuya A, Kudo C, Kadowaki T, Mayumi T, Yura Y, Kamisaki Y: PPAR γ ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice. Eur J Pharmacol 448:231-238, 2002.
78. Kaplan J, Cook JA, Hake PW, O'Connor M, Burroughs T, Zingarelli B: 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor-γ (PPARγ) ligand, reduces tissue leukosequestration and mortality in endotoxic shock. Shock 21(Suppl):32, 2004.
79. Collin M, Patel NS, Dugo L, Thiemermann C: Role of peroxisome proliferator-activated receptor-γ in the protection afforded by 15-deoxyΔ12,14 prostaglandin J2 against the multiple organ failure caused by endotoxin. Crit Care Med 32:826-831, 2004.
80. Naito Y, Yoshikawa T: Thiazolidinediones: a new class of drugs for the therapy of ischemia-reperfusion injury. Drugs Today 40:423-430, 2004.
81. Zhu P, Lu L, Xu Y, Schwartz GG: Troglitazone improves recovery of left ventricular function after regional ischemia in pigs. Circulation 101:1165-1171, 2000.
82. Khandoudi N, Delerive P, Berrebi-Bertrand I, Buckingham RE, Staels B, Bril A: Rosiglitazone, a peroxisome proliferator-activated receptor-γ, inhibits the Jun NH2-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. Diabetes 51:1507-1514, 2002.
83. Shiomi T, Tsutsui H, Hayashidani S, Suematsu N, Ikeuchi M, Wen J, Ishibashi M, Kubota T, Egashira K, Takeshita A: Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 106:3126-3132, 2002.
84. Ito H, Nakano A, Kinoshita M, Matsumori A: Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates myocardial ischemia/reperfusion injury in a rat model. Lab Invest 83: 1715-1721,2003.
85. Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C: Ligands of the peroxisome proliferator-activated receptors (PPARγ and PPARα) reduce myocardial infarct size. FASEB J 16:1027-1040, 2002.
86. Zingarelli B, Hake PW, O'Connor M, Wong HR: Peroxisome proliferator-activated receptor-γ (PPARγ) ligand, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), provides cardioprotection by modulation of the heat shock response. Crit Care Med 31(Suppl):A16, 2003.
87. Nakajima A, Wada K, Miki H, Kubota N, Nakajima N, Terauchi Y, Ohnishi S, Saubermann LJ, Kadowaki T, Blumberg RS, Nagai R, Matsuhashi N: Endogenous PPARγ mediates anti-inflammatory activity in murine ischemia-reperfusion injury. Gastroenterology 120:460-469, 2001.
88. Sivarajah A, Chatterjee PK, Patel NS, Todorovic Z, Hattori Y, Brown PA, Stewart KN, Mota-Filipe H, Cuzzocrea S, Thiemermann C: Agonists of peroxisome-proliferator activated receptor-γ reduce renal ischemia/reperfusion injury. Am J Nephrol 23:267-276, 2003.
89. Abdelrahman M, Collin M, Thiemermann C: The peroxisome proliferator-activated receptor-gamma ligand 15-deoxyΔ12,14-prostaglandin J2 reduces the organ injury in hemorrhagic shock. Shock 22:555-561, 2004.
90. Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flanigan A, Murthy S, Lazar MA, Wu GD: A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response. J Clin Invest 104:383-389, 1999.
91. Lewis JD, Lichtenstein GR, Stein RB, Deren JJ, Judge TA, Fogt F, Furth EE, Demissie EJ, Hurd LB, Su CG, Keilbaugh SA, Lazar MA, Wu GD: An open-label trial of the PPAR-γ ligand rosiglitazone for active ulcerative colitis. Am J Gastroenterol 96:3323-3328, 2001.
Keywords:

Peroxisome proliferator-activated receptor-γ; thiazolidinediones; cyclopentenone prostaglandins; signal transduction

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