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

Lewis, James D.; Lichtenstein, Gary R.; Stein, Robert B.; Deren, Julius J.; Judge, Thomas A.; Fogt, Franz; Furth, Emma E.; Demissie, Ejigayehu; Hurd, Linda B.; Su, Chinyu; Keilbaugh, Sue A.; Lazar, Mitchell A.; Wu, Gary D.

doi:10.1111/j.1572-0241.2001.05333.x

Cited by 109 publications

(74 citation statements)

References 18 publications

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“…The in vivo relevance of this endogenous PPAR␥ inflammation control is unclear at present. Synthetic PPAR␥ agonists were effective in reducing inflammation in ulcerative colitis and atherosclerosis (Su et al, 1999;Pasceri et al, 2000;Lewis et al, 2001). Mice that are PPAR␥ knockout heterozygotes are more susceptible to collagen-induced arthritis and experimental autoimmune encephalitis than wild-type littermates, indicating a clinically relevant intrinsic role for PPAR␥ in the control of inflammation (Bright et al, 2003;Cuzzocrea et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Because of these early reports, the TZDs and other synthetic PPAR␥ agonists are being studied in both animal models and human patients for their effects on inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, and multiple sclerosis (Kawahito et al, 2000;Reilly et al, 2000Reilly et al, , 2001Lewis et al, 2001;Oates et al, 2002;Duvanel et al, 2003;Kielian and Drew, 2003). The reported effective concentrations of various PPAR␥ agonists in these reports range from 10 to 50 M.…”

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confidence: 99%

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Peroxisome Proliferation-Activated Receptor (PPAR)γ Is Not Necessary for Synthetic PPARγ Agonist Inhibition of Inducible Nitric-Oxide Synthase and Nitric Oxide

Crosby

Svenson²,

Zhang³

et al. 2004

J Pharmacol Exp Ther

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Peroxisome proliferation-activated receptor (PPAR)␥ agonists inhibit inducible nitric-oxide synthase (iNOS), tumor necrosis factor-␣, and interleukin-6. Because of these effects, synthetic PPAR␥ agonists, including thiazolidinediones, are being studied for their impact on inflammatory disease. The anti-inflammatory concentrations of synthetic PPAR␥ agonists range from 10 to 50 M, whereas their binding affinity for PPAR␥ is in the nanomolar range. The specificity of synthetic PPAR␥ agonists for PPAR␥ at the concentrations necessary for anti-inflammatory effects is thus in question. We report that PPAR␥ is not necessary for the inhibition of iNOS by synthetic PPAR␥ agonists. RAW 264.7 macrophages possess little PPAR␥, yet lipopolysaccharide (LPS)/interferon (IFN)␥-induced iNOS was inhibited by synthetic PPAR␥ agonists at 20 M. Endogenous PPAR␥ was inhibited by the transfection of a dominant-negative PPAR␥ construct into murine mesangial cells. In the transfected cells, synthetic PPAR␥ agonists inhibited iNOS production at 10 M, similar to nontransfected cells. Using cells from PPAR␥ Cre/lox conditional knockout mice, baseline and LPS/ IFN␥-induced nitric oxide levels were higher in macrophages lacking PPAR␥ versus controls. However, synthetic PPAR␥ agonists inhibited iNOS at 10 M in the PPAR␥-deficient cells, similar to macrophages from wild-type mice. These results indicate that PPAR␥ is not necessary for inhibition of iNOS expression by synthetic PPAR␥ agonists at concentrations over 10 M. Intrinsic PPAR␥ function, in the absence of synthetic agonists, however, may play a role in inflammatory modulation.Synthetic agonists of peroxisome proliferation-activated receptor (PPAR)␥, known as thiazolidinediones (TZDs), are currently being used for treatment of type II diabetes. Their clinical efficacy in diabetes coupled with the early reports of their effect on inflammatory mediator reduction in macrophage cell lines has lead to the study of PPAR␥ as an endogenous modulator of inflammation. The intrinsic ligand for PPAR␥ remains unclear. A prostaglandin J 2 metabolite was proposed to be an endogenous PPAR␥ agonist. This metabolite was shown effective at reducing markers of inflammation, such as inducible nitric-oxide synthase (iNOS), at concentrations less than 10 M (Jiang et al., 1998;Ricote et al., 1998;Petrova et al., 1999). However, it was later shown that in addition to binding to PPAR␥, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15dPGJ 2 ) also stabilized NF-B and prevented its activation of the iNOS promoter (Straus et al., 2000). A reactive metabolite, 15dPGJ 2 is capable of donating an electron to the NF-B. Recently, the lack of physiologic relevance of 15dPGJ 2 as an endogenous PPAR␥ agonist was demonstrated, and toxicity of the compound limits its clinical utility (Bell-Parikh et al., 2003). Thus, it is clear from a number of studies that PPAR␥ is not necessary for the anti-inflammatory properties of 15dPGJ 2 . This same PPAR␥-independent reactivity has not been reported for the synthetic PPAR␥ agonists s...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Peroxisome Proliferation-Activated Receptor (PPAR)γ Is Not Necessary for Synthetic PPARγ Agonist Inhibition of Inducible Nitric-Oxide Synthase and Nitric Oxide

Crosby

Svenson²,

Zhang³

et al. 2004

J Pharmacol Exp Ther

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“…Since recent in vitro and animal model studies have implicated PPAR-γ ligands as potential modulators of inflammation-related diseases such as inflammatory bowel disease, psoriasis and rheumatoid arthritis, (48)(49)(50), their use in endometriosis is not far-fetched. Several in vitro studies with thiazolidinediones (TZDs) and endometriotic cells (15,39) led to their use in endometriosis animal models.…”

Section: Discussionmentioning

confidence: 99%

PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: A prospective, randomized, placebo- and drug-controlled study

Lebovic

Mwenda

Chai

et al. 2007

Fertility and Sterility

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Objective-To determine the effects of a thiazolidinedione (TZD) agonist of peroxisome proliferator-activated receptor (PPAR)-γ, rosiglitazone, in a baboon model of established endometriosis.Design-Prospective, randomized, placebo-controlled study.Setting-Experimental surgery laboratory at the Institute of Primate Research in Nairobi, Kenya.Animal(s)-Endometriosis was induced using intrapelvic injection of eutopic menstrual endometrium in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity.Intervention(s)-Induction of endometriosis by laparoscopy was performed in 12 baboons with a normal pelvis. Endometrial tissue was extracted from each baboon by curettage and a standard amount of endometrium was then seeded onto several peritoneal sites as previously described. About 34-68 days after the induction of laparoscopy, a pre-treatment laparoscopy (baseline disease assessment) was performed in the baboons to record the extent of endometriotic lesions. The 12 baboons were randomized into 3 groups and treated from the day after the staging laparoscopy for a total duration of 30 days. They received either PBS tablets (n=4, placebo control; placebo tablets once a day by mouth for 30 days), GnRH-antagonists (n=4, active control; Ganirelix acetate 125 μg/day for 30 days) or rosiglitazone (n=4, test drug, 2 mg by mouth each day for 30 days). A 3 rd and final laparoscopy on day 30 after the start of treatment was performed to record the extent of endometriosis. The type of lesion (typical, red, white and suspicious) was recorded. Biopsies were obtained to confirm the histological presence of endometriosis.Main Outcome Measure(s)-A videolaparoscopy was performed 30 days after treatment to document the number and surface area of endometriotic lesions as well as to calculate the revised American Society for Reproductive Medicine score (rAFS) and stage.Corresponding author Dan I. Lebovic, M.D., M.A., Department of Obstetrics and Gynecology, University of Michigan, Tel: 734-615-8257, Fax: 734-647-1006, E-mail: lebovic@umich.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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“…Agonists of PPAR␥, 15d-PGJ2, and the antidiabetic rosiglitazone have been shown to suppress JAK/STAT signal- ing through the induction of SOCS1 and SOCS3, which are suppressors of cytokine signaling (38). Accordingly, PPAR␥ ligands have been shown to markedly reduce colonic inflammation in a mouse model of IBD (68,69) and to inhibit Rasmediated transformation of intestinal cells (70).…”

Section: Discussionmentioning

confidence: 99%

Requirement of Histone Deacetylase Activity for Signaling by STAT1

Klampfer

Huang

Swaby

et al. 2004

Journal of Biological Chemistry

172

151

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STAT1 is a transcription factor that plays a crucial role in signaling by interferons (IFNs). In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFN␥-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation. Furthermore, we showed that silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFN␥-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity. Our data therefore established the essential role of deacetylase activity in STAT1 signaling. Induction of IRF-1 by IFN␥ requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA. In contrast, silencing of STAT1 did not interfere with IFN␥-induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFN␥-induced expression of STAT1, STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFN␥ target genes whose expression depends on STAT1 but do not interfere with STAT1-independent signaling by IFN␥. Finally, we showed that inhibitors of deacetylase activity sensitized colon cancer cells to IFN␥-induced apoptosis through cooperative negative regulation of Bcl-x expression, demonstrating that interruption of the balance between STAT1-dependent and STAT1-independent signaling significantly alters the biological activity of IFN␥.

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

Abstract: These data suggest that ligands for the gamma subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.

Cited by 109 publications

References 18 publications

Peroxisome Proliferation-Activated Receptor (PPAR)γ Is Not Necessary for Synthetic PPARγ Agonist Inhibition of Inducible Nitric-Oxide Synthase and Nitric Oxide

Peroxisome Proliferation-Activated Receptor (PPAR)γ Is Not Necessary for Synthetic PPARγ Agonist Inhibition of Inducible Nitric-Oxide Synthase and Nitric Oxide

PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: A prospective, randomized, placebo- and drug-controlled study

Requirement of Histone Deacetylase Activity for Signaling by STAT1

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