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Signal pathways JNK and NF-kappa B, identified by global gene expression profiling, are involved in regulation of TNF alpha-induced mPGES-1 and COX-2 expression in gingival fibroblasts
KTH, School of Biotechnology (BIO), Gene Technology.
KTH, School of Biotechnology (BIO), Gene Technology.
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2010 (English)In: BMC Genomics, ISSN 1471-2164, Vol. 11, 241- p.Article in journal (Refereed) Published
Abstract [en]

Background: Prostaglandin E-2 (PGE(2)) is involved in several chronic inflammatory diseases including periodontitis, which causes loss of the gingival tissue and alveolar bone supporting the teeth. We have previously shown that tumor necrosis factor a (TNF alpha) induces PGE(2) synthesis in gingival fibroblasts. In this study we aimed to investigate the global gene expression profile of TNF alpha-stimulated primary human gingival fibroblasts, focusing on signal pathways related to the PGE(2)-synthesizing enzymes prostaglandin E synthases (PGES), as well as the upstream enzyme cyclooxygenase-2 (COX-2) and PGE(2) production. Results: Microarray and western blot analyses showed that the mRNA and protein expression of the inflammatory induced microsomal prostaglandin E synthase-1 (mPGES-1) was up-regulated by the cytokine TNF alpha, accompanied by enhanced expression of COX-2 and increased production of PGE(2). In contrast, the expression of the isoenzymes microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNF alpha treatment. Using oligonucleotide microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, differentially expressed genes in response to TNF alpha treatment were identified. Enrichment analysis of microarray data indicated two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappa B (NF-kappa B). To evaluate their involvement in the regulation of mPGES-1 and COX-2 expression, we used specific inhibitors as well as phosphorylation analysis. Phosphorylation analysis of JNK (T183/Y185) and NF-kappa B p65 (S536) showed increased phosphorylation in response to TNF alpha treatment, which was decreased by specific inhibitors of JNK (SP600125) and NF-kappa B (Bay 11-7082, Ro 106-9920). Inhibitors of JNK and NF-kappa B also decreased the TNF alpha-stimulated up-regulation of mPGES-1 and COX-2 as well as PGE(2) production. Conclusion: In the global gene expression profile, the enrichment analysis of microarray data identified the two signal transduction pathways JNK and NF-kappa B as positively regulated by the cytokine TNF alpha. Inhibition of these TNF alpha-activated signal pathways reduced the expression of mPGES-1 and COX-2 as well as their end product PGE(2) in gingival fibroblasts. The involvement of the signal pathways JNK and NF-kappa B in the regulation of PGE(2) induced by TNF alpha may suggest these two pathways as possible attractive targets in the chronic inflammatory disease periodontitis.

Place, publisher, year, edition, pages
2010. Vol. 11, 241- p.
Keyword [en]
National Category
Industrial Biotechnology
URN: urn:nbn:se:kth:diva-27597DOI: 10.1186/1471-2164-11-241ISI: 000277991100001ScopusID: 2-s2.0-77950833537OAI: diva2:377145
QC 20101213Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2010-12-13Bibliographically approved

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Lindberg, JohanLundeberg, Joakim
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