Diabetes, Vol 49, Issue 3 346-355, Copyright © 2000 by American Diabetes Association

ARTICLES

Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone: evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression

LB Maggi, H Sadeghi, C Weigand, AL Scarim, MR Heitmeier and JA Corbett
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Missouri 63104, USA.

In this study, the anti-inflammatory actions of the peroxisome proliferator-activated receptor (PPAR)-gamma agonists 15-deoxy-delta 12,14-prostaglandin J2 (15-d-delta 12,14-PGJ2) and troglitazone have been examined. Treatment of RAW 264.7 cells and CD-1 mouse peritoneal macrophages with lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) results in inducible nitric oxide synthase (iNOS), inducible cyclooxygenase (COX-2) and interleukin-1 (IL-1) expression, increased production of nitric oxide, and the release of IL-1. In a concentration-dependent manner, 15-d-delta 12,14-PGJ2 inhibits each of these proinflammatory actions of LPS + IFN-gamma, with half-maximal inhibition at approximately 0.5 microg/ml and complete inhibition at 1-5 microg/ml. The inhibitory actions of 15-d-delta 12,14-PGJ2 on LPS + IFN-gamma-induced inflammatory events are not associated with the inhibition of iNOS enzymatic activity or macrophage cell death, but appear to result from an inhibition of iNOS and IL-1 transcription. In addition, the anti-inflammatory actions of 15-d-delta 12,14-PGJ2 are not limited to peritoneal macrophages, as 15-d-delta 12,14-PGJ2 prevents TNF-alpha + LPS-induced resident islet macrophage expression of IL-1beta and beta-cell expression of iNOS stimulated by the local release of IL-1 in rat islets. 15-d-delta 12,14-PGJ2 appears to be approximately 10-fold more effective at inhibiting resident islet macrophage activation (in response to TNF + LPS) than IL-1-induced nitrite production by beta-cells. Two mechanisms appear to be associated with the antiinflammatory actions of both 15-d-delta 12,14-PGJ2 and troglitazone: 1) the direct inhibition of cytokine- and endotoxin-stimulated iNOS and IL-1 transcription; and 2) the inhibition of IL-1 signaling, an event associated with PPAR-gamma agonist-induced activation of the heat shock response (as assayed by heat shock protein 70 expression). These findings indicate that the PPAR-gamma agonists, troglitazone and the J series of prostaglandins, are potent anti-inflammatory agents that prevent cytokine- and endotoxin-stimulated activation of peripheral and resident tissue macrophages and cytokine-induced iNOS expression by beta-cells by the inhibition of transcriptional activation and induction of the heat shock response.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				P. Dallaire, K. Bellmann, M. Laplante, S. Gelinas, C. Centeno-Baez, P. Penfornis, M.-L. Peyot, M. G. Latour, J. Lamontagne, M. E. Trujillo, et al. Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator-Activated Receptor-{gamma} Agonism Diabetes, August 1, 2008; 57(8): 1999 - 2011. [Abstract] [Full Text] [PDF]

				K. T. Chambers, S. M. Weber, and J. A. Corbett PGJ2-stimulated beta-cell apoptosis is associated with prolonged UPR activation Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1052 - E1061. [Abstract] [Full Text] [PDF]

				R. Luna-Medina, M. Cortes-Canteli, M. Alonso, A. Santos, A. Martinez, and A. Perez-Castillo Regulation of Inflammatory Response in Neural Cells in Vitro by Thiadiazolidinones Derivatives through Peroxisome Proliferator-activated Receptor {gamma} Activation J. Biol. Chem., June 3, 2005; 280(22): 21453 - 21462. [Abstract] [Full Text] [PDF]

				M. Fujimoto, N. Shimizu, K. Kunii, J.A. J. Martyn, K. Ueki, and M. Kaneki A Role for iNOS in Fasting Hyperglycemia and Impaired Insulin Signaling in the Liver of Obese Diabetic Mice Diabetes, May 1, 2005; 54(5): 1340 - 1348. [Abstract] [Full Text] [PDF]

				M. A. Carvalho-Filho, M. Ueno, S. M. Hirabara, A. B. Seabra, J. B.C. Carvalheira, M. G. de Oliveira, L. A. Velloso, R. Curi, and M. J.A. Saad S-Nitrosation of the Insulin Receptor, Insulin Receptor Substrate 1, and Protein Kinase B/Akt: A Novel Mechanism of Insulin Resistance Diabetes, April 1, 2005; 54(4): 959 - 967. [Abstract] [Full Text] [PDF]

				S. M. Weber, K. T. Chambers, K. G. Bensch, A. L. Scarim, and J. A. Corbett PPAR{gamma} ligands induce ER stress in pancreatic {beta}-cells: ER stress activation results in attenuation of cytokine signaling Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1171 - E1177. [Abstract] [Full Text] [PDF]

				O. Hofnagel, B. Luechtenborg, K. Stolle, S. Lorkowski, H. Eschert, G. Plenz, and H. Robenek Proinflammatory Cytokines Regulate LOX-1 Expression in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1789 - 1795. [Abstract] [Full Text] [PDF]

				S. M. Weber, A. L. Scarim, and J. A. Corbett PPAR{gamma} is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic {beta}-cells Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E329 - E336. [Abstract] [Full Text]

				T. Kumagai, T. Ikezoe, D. Gui, J. O'Kelly, X.-J. Tong, F. J. Cohen, J. W. Said, and H. P. Koeffler RWJ-241947 (MCC-555), A Unique Peroxisome Proliferator-Activated Receptor-{gamma} Ligand with Antitumor Activity against Human Prostate Cancer in Vitro and in Beige/Nude/ X-Linked Immunodeficient Mice and Enhancement of Apoptosis in Myeloma Cells Induced by Arsenic Trioxide Clin. Cancer Res., February 15, 2004; 10(4): 1508 - 1520. [Abstract] [Full Text] [PDF]

				A. Mouihate, L. Boisse, and Q. J. Pittman A Novel Antipyretic Action of 15-Deoxy-{Delta}12,14-Prostaglandin J2 in the Rat Brain J. Neurosci., February 11, 2004; 24(6): 1312 - 1318. [Abstract] [Full Text] [PDF]

				D. Perez-Sala, E. Cernuda-Morollon, and F. J. Canada Molecular Basis for the Direct Inhibition of AP-1 DNA Binding by 15-Deoxy-{Delta}12,14-prostaglandin J2 J. Biol. Chem., December 19, 2003; 278(51): 51251 - 51260. [Abstract] [Full Text] [PDF]

				B. Zingarelli, M. Sheehan, P. W. Hake, M. O'Connor, A. Denenberg, and J. A. Cook Peroxisome Proliferator Activator Receptor-{gamma} Ligands, 15-Deoxy-{Delta}12,14-Prostaglandin J2 and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways J. Immunol., December 15, 2003; 171(12): 6827 - 6837. [Abstract] [Full Text] [PDF]

				A. L. Scarim, S. Y. Nishimoto, S. M. Weber, and J. A. Corbett Role for c-Jun N-Terminal Kinase in {beta}-Cell Recovery from Nitric Oxide-Mediated Damage Endocrinology, August 1, 2003; 144(8): 3415 - 3422. [Abstract] [Full Text] [PDF]

				S. M. Weber, A. L. Scarim, and J. A. Corbett Inhibition of IFN-gamma -induced STAT1 activation by 15- deoxy-Delta 12,14-prostaglandin J2 Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E883 - E891. [Abstract] [Full Text] [PDF]

				A. Nencioni, F. Grunebach, A. Zobywlaski, C. Denzlinger, W. Brugger, and P. Brossart Dendritic Cell Immunogenicity Is Regulated by Peroxisome Proliferator-Activated Receptor {gamma} J. Immunol., August 1, 2002; 169(3): 1228 - 1235. [Abstract] [Full Text] [PDF]

				N. Khandoudi, P. Delerive, I. Berrebi-Bertrand, R. E. Buckingham, B. Staels, and A. Bril Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-{gamma}, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury Diabetes, May 1, 2002; 51(5): 1507 - 1514. [Abstract] [Full Text] [PDF]

				S. G. Harris, R. S. Smith, and R. P. Phipps 15-Deoxy-{Delta}12,1412,14-PGJ2 Induces IL-8 Production in Human T Cells by a Mitogen-Activated Protein Kinase Pathway J. Immunol., February 1, 2002; 168(3): 1372 - 1379. [Abstract] [Full Text] [PDF]

				B. H. ROVIN, L. LU, and A. COSIO Cyclopentenone Prostaglandins Inhibit Cytokine-Induced NF-{kappa}B Activation and Chemokine Production by Human Mesangial Cells J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1659 - 1667. [Abstract] [Full Text] [PDF]

				K. Guyton, R. Bond, C. Reilly, G. Gilkeson, P. Halushka, and J. Cook Differential effects of 15-deoxy-{Delta}12,14-prostaglandin J2 and a peroxisome proliferator-activated receptor {gamma} agonist on macrophage activation J. Leukoc. Biol., April 1, 2001; 69(4): 631 - 638. [Abstract] [Full Text]

				C. Thevenon, M. Guichardant, and M. Lagarde Gas Chromatographic-Mass Spectrometric Measurement of 15-Deoxy-{{Delta}}12,14-prostaglandin J2, the Peroxisome Proliferator-activated Receptor {{gamma}} Ligand, in Urine Clin. Chem., April 1, 2001; 47(4): 768 - 770. [Full Text] [PDF]

				H. Ghanim, R. Garg, A. Aljada, P. Mohanty, Y. Kumbkarni, E. Assian, W. Hamouda, and P. Dandona Suppression of Nuclear Factor-{{kappa}}B and Stimulation of Inhibitor {{kappa}}B by Troglitazone: Evidence for an Anti-inflammatory Effect and a Potential Antiatherosclerotic Effect in the Obese J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1306 - 1312. [Abstract] [Full Text]

				T. Tanaka, H. Kohno, S.-i. Yoshitani, S. Takashima, A. Okumura, A. Murakami, and M. Hosokawa Ligands for Peroxisome Proliferator-activated Receptors {{alpha}} and {{gamma}} Inhibit Chemically Induced Colitis and Formation of Aberrant Crypt Foci in Rats1 Cancer Res., March 1, 2001; 61(6): 2424 - 2428. [Abstract] [Full Text]