Activation of Retinoic X Receptor and Peroxisome Proliferator-Activated Receptor–γ Inhibits Nitric Oxide and Tumor Necrosis Factor–α Production in Rat Kupffer Cells

Uchimura, Koutaro

doi:10.1053/jhep.2001.21145

Cited by 118 publications

(84 citation statements)

References 36 publications

(61 reference statements)

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“…Previous reports have shown that the induction of MCP-1 by PMA, serving as a protein kinase C activator, can be detected in various other cell types (Haslinger et al, 2001;Kakizaki et al, 1995). This effect of the TZD compound on inhibition of proinflammatory cytokines is observed with different kinds of TZDs currently used in clinical medicine (Su et al, 1999;Uchimura et al, 2001). It is, however, noteworthy that the potency of TZDs varies widely depending on the form of these compounds.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, we have found that pioglitazone does not modify nuclear factor-B activity in luciferase assay using A549 cells, a human epithelium-like lung carcinoma cell line stimulated with PMA (data not shown). At this point, troglitazone is known to inhibit nuclear factor-B activity and sequentially suppress proinflammatory cytokine production in several cell types (Desreumaux et al, 2001;Uchimura et al, 2001). This difference could be caused by variations in the amount of specific coactivators or other mechanisms independent of PPAR-␥ activation.…”

Section: Discussionmentioning

confidence: 99%

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Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model

Ito

Nakano

Kinoshita

et al. 2003

Laboratory Investigation

101

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SUMMARY:Thiazolidinediones are insulin-sensitizing drugs, ligands for peroxisome proliferator-activated receptor-␥ (PPAR-␥), which play an important role in the modulation of inflammatory responses. Myocardial ischemia/reperfusion (MI/R) injury is associated with inflammation, in which various cells, particularly monocytes and macrophages, are involved. This study examined the effects of the thiazolidinedione peroxisome proliferator-activated receptor-␥ ligand, pioglitazone, in a rat model of MI/R injury. Pioglitazone at 3 mg/kg/day or the vehicle was administered for 7 days before rats were subjected to 30 minutes of coronary ligation followed by 24 hours of reperfusion. The mRNA expression [monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1] in the ischemic region, the number of infiltrating macrophages in the ischemic region, and the myocardial infarct size were examined. The inhibitory effects of pioglitazone on activated macrophages were studied in vitro. Phorbol 12-myristate 13-acetate-induced MCP-1 production, in the absence or presence of pioglitazone, were assayed in cultured macrophages. Compared with the control group, (1) mRNA levels of MCP-1 and intercellular adhesion molecule-1 and the number of infiltrating macrophages in the ischemic region were significantly lower in the pioglitazone-treated group; and (2) myocardial infarct size was significantly smaller in the pioglitazone-treated group. Phorbol 12-myristate 13-acetate-stimulated cultured macrophages in the presence of pioglitazone produced significantly lower levels of MCP-1 than the stimulated control in the absence of pioglitazone. These observations demonstrate that pioglitazone has anti-inflammatory effects in MI/R injury that are independent of its insulin-sensitizing effect. (Lab Invest 2003, 83:1715-1721.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model

Ito

Nakano

Kinoshita

et al. 2003

Laboratory Investigation

101

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“…These include cytokines, cell adhesion molecules, and other proinflammatory signaling molecules such as iNOS. 15,17,44 Further, different regulation of PPRE binding in fatty and lean livers may result in different recruitment of coactivators and dissociation of corepressors upon combined stimulation with alcohol and LPS. PPARs were shown in in vitro studies to inhibit activation of various proinflammatory cascades and nuclear regulatory factors (mitogen-activated protein kinase, NF-B, AP-1, and nuclear factor of activated T cells).…”

Section: Discussionmentioning

confidence: 99%

“…14 Other studies have demonstrated that PPAR-␥ ligands can inhibit inflammatory responses by decreasing IL-6, TNF-␣, IL-1␤ secretion, and inducible nitric-oxide synthetase (iNOS) production in macrophages and Kupffer cells. 15,16 Both PPAR-␣ and PPAR-␥ inhibit inflammation by interfering with nuclear factor-B (NF-B) and activator protein 1 (AP-1) transactivation through a direct protein-protein interaction with p65 or c-Jun, respectively. 17,18 In addition, PPAR-␣ activators up-regulate inhibitory B (I B)-␣ in many cell types.…”

mentioning

confidence: 99%

Diverse regulation of NF-κB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver

et al. 2004

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Fatty liver is highly sensitive to inflammatory activation. Peroxisome proliferator-activated receptors (PPAR) have anti-inflammatory effects and regulate lipid metabolism in the fatty liver. We hypothesized that fatty liver leads to endotoxin sensitivity through an imbalance between pro-and anti-inflammatory signals. Leptin-deficient, ob/ob mice and their lean littermates were challenged with single or double insults and pro-and anti-inflammatory pathways were tested on cytokine production and activation of nuclear regulatory factors NF-B and peroxisome proliferator receptor element (PPRE). Ob/ob mice produced significantly higher serum tumor necrosis factor ␣ (TNF-␣) and interleukin (

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“…There is increasing evidence to support a protective role of PPARγ in various pathophysiological conditions including cancer, atherosclerosis, diabetes and hepatogastroenterological diseases [19,21]. PPARγ ligands can inhibit LPS-induced NO and TNFα production in cultured KCs and the inhibition was potentiated by co-treatment with RXR agonists [22]. However, it is not known whether PPARγ agonists have any role in reducing the effects of inflammation on NR genes in hepatocytes, although recent studies in humans with non-alcoholic steatohepatitis (NASH) support PPARγ ligands as potential anti-inflammatory agents [23,24].…”

Section: Introductionmentioning

confidence: 99%

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Ghose

Mulder

Furstenberg

et al. 2007

Journal of Hepatology

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Background/Aims-A recently-determined target of lipopolysaccharide (LPS) and cytokine signaling in liver is the central Type II nuclear receptor (NR) heterodimer partner, Retinoid X receptor α (RXRα). We sought to determine if rosiglitazone (Rosi) a peroxisome proliferator activated receptor γ(PPARγ) agonist with anti-inflammatory properties, can attenuate LPS and cytokineinduced molecular suppression of RXRα-regulated genes.Methods-In vivo, mice were gavage-fed Rosi for 3 days, prior to intraperitoneal injection of LPS, followed by harvest of liver and serum. In vitro, HepG2 cells were treated with IL-1β, ± short-term Rosi pretreatment. RNA was analyzed by quantitative RT-PCR, while nuclear and cytoplasmic proteins were analyzed by immunoblotting and gel shifts.Results-Rosi attenuated LPS-mediated suppression of RNA levels of several Type II NRregulated genes, including bile acid transporters and the major drug metabolizing enzyme, Cyp3a11, without affecting cytokine expression, suggesting a novel, direct anti-inflammatory effect in hepatocytes. Rosi suppressed the inflammation-induced nuclear export of RXRα, in both LPSinjected mice and IL-1β-treated HepG2 cells, leading to maintenance of nuclear RXRα levels and heterodimer binding activity.Conclusions-Rosi directly attenuates the suppressive effects of inflammation-induced cell signaling on nuclear RXRα levels in liver.

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Activation of Retinoic X Receptor and Peroxisome Proliferator-Activated Receptor–γ Inhibits Nitric Oxide and Tumor Necrosis Factor–α Production in Rat Kupffer Cells

Cited by 118 publications

References 36 publications

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model

Diverse regulation of NF-κB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

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