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J. Biol. Chem., Vol. 279, Issue 34, 36103-36111, August 20, 2004

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15-Deoxy-^12,14-prostaglandin J₂-mediated ERK Signaling Inhibits Gram-negative Bacteria-induced RelA Phosphorylation and Interleukin-6 Gene Expression in Intestinal Epithelial Cells through Modulation of Protein Phosphatase 2A Activity^*

Pedro A. Ruiz, Sandra C. Kim¶, R. Balfour Sartor¶||, and Dirk Haller**

From the Centre for Nutrition and Food Research, Immunobiology of Nutrition, Technical University of Munich, 85350 Freising-Weihenstephan, Germany and Department of Pediatrics, ^||Departments of Medicine, Microbiology, and Immunology, and ^¶the Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina 27599

We have previously shown that non-pathogenic Gram-negative Bacteroides vulgatus induces transient RelA phosphorylation (Ser-536), NF-B activity, and pro-inflammatory gene expression in native and intestinal epithelial cell (IEC) lines. We now demonstrate that 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) but not prostaglandin E₂ inhibits lipopolysaccharide (LPS) (B. vulgatus)/LPS (Escherichia coli)-induced RelA phosphorylation and interleukin-6 gene expression in the colonic epithelial cell line CMT-93. This inhibitory effect of 15d-PGJ₂ was mediated independently of LPS-induced IB phosphorylation/degradation and RelA nuclear translocation as well as RelA DNA binding activity. Interestingly, although B. vulgatus induced nuclear expression of peroxisome proliferator-activated receptor (PPAR) in native epithelium of monoassociated Fisher rats, PPAR-specific knock-down in CMT-93 cells using small interference RNA failed to reverse the inhibitory effects of PPAR agonist 15d-PGJ₂, suggesting PPAR-independent mechanisms. In addition, 15d-PGJ₂ but not the synthetic high affinity PPAR ligand rosiglitazone triggered ERK1/2 phosphorylation in IEC, and most importantly, MEK1 inhibitor PD98059 reversed the inhibitory effect of 15dPGJ₂ on LPS-induced RelA phosphorylation and interleukin-6 gene expression. Calyculin A, a specific phosphoserine/phospho-threonine phosphatase inhibitor increased the basal phosphorylation of RelA and reversed the inhibitory effect of 15d-PGJ₂ on LPS-induced RelA phosphorylation. We further demonstrated in co-immunoprecipitation experiments that 15d-PGJ₂ triggered protein phosphatase 2A activity, which directly dephosphorylated RelA in LPS-stimulated CMT-93 cells. We concluded that 15d-PGJ₂ may help to control NF-B signaling and normal intestinal homeostasis to the enteric microflora by modulating RelA phosphorylation in IEC through altered protein phosphatase 2A activity.

Received for publication, May 6, 2004 , and in revised form, June 14, 2004.

^* This work was supported by Die Deutsche Forschungsgemeinschaft Grant HA 3148/1-2 (to D. H.), by National Institutes of Health Grants RO1 DK53347 and P30 DK34987 (to R. B. S.), and by the Crohn's and Colitis Foundation of America (to S. C. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 49-8161-71-2026; Fax: 49-8161-71-3999; E-mail: haller{at}wzw.tum.de.

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