Expression of Peroxisome Proliferator-activated Receptor-gamma in Macrophage Suppresses Experimentally Induced Colitis

Overview

Journal Am J Physiol Gastrointest Liver Physiol

Publisher American Physiological Society

Specialties Gastroenterology
Physiology

Date 2006 Nov 11

PMID 17095756

Citations 54

Authors

Yatrik M Shah

Keiichirou Morimura

Frank J Gonzalez

Affiliations

Soon will be listed here.

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR-gamma is expressed in several different cell types, and mice with a targeted disruption of the PPAR-gamma gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium (DSS)-induced IBD. However, the highly selective PPAR-gamma ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR-gamma intestinal specific null mice and wild-type littermates. Therefore the role of PPAR-gamma in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR-gamma in macrophages (PPAR-gamma(DeltaMphi)) and wild-type littermates (PPAR-gamma(F/F)) were administered 2.5% DSS in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis, and proinflammatory cytokine analysis was performed. PPAR-gamma(DeltaMphi) mice displayed an increased susceptibility to DSS-induced colitis compared with wild-type littermates, as defined by body weight loss, diarrhea, rectal bleeding score, colon length, and histology. IL-1beta, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR-gamma(DeltaMphi) mice treated with DSS were higher than in similarly treated PPAR-gamma(F/F) mice. The present study has identified a novel protective role for macrophage PPAR-gamma in the DSS-induced IBD model. The data suggest that PPAR-gamma regulates recruitment of macrophages to inflammatory foci in the colon.

Citing Articles

PPAR-γ agonist mitigates intestinal barrier dysfunction and inflammation induced by Clostridioides difficile SlpA in vitro.

Noori M, Azimirad M, Ghorbaninejad M, Meyfour A, Zali M, Yadegar A Sci Rep. 2024; 14(1):32087.

PMID: 39738433 PMC: 11686163. DOI: 10.1038/s41598-024-83815-4.

Harnessing nature's pharmacy: investigating natural compounds as novel therapeutics for ulcerative colitis.

Huang Y, Wu Q, Li S, Lin X, Yang S, Zhu R Front Pharmacol. 2024; 15:1394124.

PMID: 39206263 PMC: 11349575. DOI: 10.3389/fphar.2024.1394124.

Peroxisome proliferator-activated receptor-γ as the gatekeeper of tight junction in infection.

Lai Y, Wu T, Tsai B, Hung Y, Lin H, Tsai Y Front Microbiol. 2022; 13:986457.

PMID: 36439832 PMC: 9691888. DOI: 10.3389/fmicb.2022.986457.

Physiological Convergence and Antagonism Between GR and PPARγ in Inflammation and Metabolism.

Dacic M, Shibu G, Rogatsky I Adv Exp Med Biol. 2022; 1390:123-141.

PMID: 36107316 DOI: 10.1007/978-3-031-11836-4_7.

Colonic Medium-Chain Fatty Acids Act as a Source of Energy and for Colon Maintenance but Are Not Utilized to Acylate Ghrelin.

Gregor A, Auernigg-Haselmaier S, Trajanoski S, Konig J, Duszka K Nutrients. 2021; 13(11).

PMID: 34836064 PMC: 8617845. DOI: 10.3390/nu13113807.

References

Spiegelman B, Hu E, Kim J, Brun R . PPAR gamma and the control of adipogenesis. Biochimie. 1997; 79(2-3):111-2. DOI: 10.1016/s0300-9084(97)81500-3. View

Kliewer S, Sundseth S, Jones S, Brown P, Wisely G, Koble C . Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997; 94(9):4318-23. PMC: 20720. DOI: 10.1073/pnas.94.9.4318. View

Zingarelli B, Cuzzocrea S, Szabo C, Salzman A . Mercaptoethylguanidine, a combined inhibitor of nitric oxide synthase and peroxynitrite scavenger, reduces trinitrobenzene sulfonic acid-induced colonic damage in rats. J Pharmacol Exp Ther. 1998; 287(3):1048-55. View

Gosling J, Slaymaker S, Gu L, Tseng S, Zlot C, Young S . MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest. 1999; 103(6):773-8. PMC: 408147. DOI: 10.1172/JCI5624. View

Dawson T, Kuziel W, Osahar T, Maeda N . Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis. 1999; 143(1):205-11. DOI: 10.1016/s0021-9150(98)00318-9. View

Su C, Wen X, Bailey S, Jiang W, Rangwala S, Keilbaugh S . A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest. 1999; 104(4):383-9. PMC: 408529. DOI: 10.1172/JCI7145. View

Weber C, Schober A, Zernecke A . Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease. Arterioscler Thromb Vasc Biol. 2004; 24(11):1997-2008. DOI: 10.1161/01.ATV.0000142812.03840.6f. View

Suschek C, Schnorr O, Kolb-Bachofen V . The role of iNOS in chronic inflammatory processes in vivo: is it damage-promoting, protective, or active at all?. Curr Mol Med. 2004; 4(7):763-75. DOI: 10.2174/1566524043359908. View

Tanaka T, Fukunaga Y, Itoh H, Doi K, Yamashita J, Chun T . Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor gamma for monocyte recruitment and endothelial regeneration. Eur J Pharmacol. 2005; 508(1-3):255-65. DOI: 10.1016/j.ejphar.2004.10.056. View

10.

Lytle C, Tod T, Vo K, Lee J, Atkinson R, Straus D . The peroxisome proliferator-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency. Inflamm Bowel Dis. 2005; 11(3):231-43. DOI: 10.1097/01.mib.0000160805.46235.eb. View

11.

Jones J, Barrick C, Kim K, Lindner J, Blondeau B, Fujimoto Y . Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A. 2005; 102(17):6207-12. PMC: 556131. DOI: 10.1073/pnas.0306743102. View

12.

Chen Y, Green S, Ho J, Li A, Almazan F, Quehenberger O . The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor gamma ligands. Biochem Biophys Res Commun. 2005; 332(1):188-93. DOI: 10.1016/j.bbrc.2005.04.110. View

13.

Sanchez-Hidalgo M, Martin A, Villegas I, Alarcon de La Lastra C . Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces chronic colonic inflammation in rats. Biochem Pharmacol. 2005; 69(12):1733-44. DOI: 10.1016/j.bcp.2005.03.024. View

14.

Crosby M, Svenson J, Gilkeson G, Nowling T . A novel PPAR response element in the murine iNOS promoter. Mol Immunol. 2005; 42(11):1303-10. DOI: 10.1016/j.molimm.2004.12.009. View

15.

Tokuyama H, Ueha S, Kurachi M, Matsushima K, Moriyasu F, Blumberg R . The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis. Int Immunol. 2005; 17(8):1023-34. DOI: 10.1093/intimm/dxh284. View

16.

Babaev V, Yancey P, Ryzhov S, Kon V, Breyer M, Magnuson M . Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2005; 25(8):1647-53. DOI: 10.1161/01.ATV.0000173413.31789.1a. View

17.

Pascual G, Fong A, Ogawa S, Gamliel A, Li A, Perissi V . A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005; 437(7059):759-63. PMC: 1464798. DOI: 10.1038/nature03988. View

18.

Kobayashi M, Thomassen M, Rambasek T, Bonfield T, Raychaudhuri B, Malur A . An inverse relationship between peroxisome proliferator-activated receptor gamma and allergic airway inflammation in an allergen challenge model. Ann Allergy Asthma Immunol. 2005; 95(5):468-73. DOI: 10.1016/S1081-1206(10)61173-8. View

19.

Adachi M, Kurotani R, Morimura K, Shah Y, Sanford M, Madison B . Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut. 2006; 55(8):1104-13. PMC: 1513267. DOI: 10.1136/gut.2005.081745. View

20.

Rosen E, Sarraf P, Troy A, Bradwin G, Moore K, Milstone D . PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999; 4(4):611-7. DOI: 10.1016/s1097-2765(00)80211-7. View