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J. Biol. Chem., Vol. 281, Issue 25, 16985-16990, June 23, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/25/16985    most recent M602446200v2 M602446200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vines, A. Articles by Pillarisetti, S. Search for Related Content PubMed PubMed Citation Articles by Vines, A. Articles by Pillarisetti, S. Social Bookmarking                      What's this?

Novel Anti-inflammatory Role for Glycogen Synthase Kinase-3 in the Inhibition of Tumor Necrosis Factor-- and Interleukin-1-induced Inflammatory Gene Expression^*

Angela Vines¹, Sientay Cahoon, Ira Goldberg, Uday Saxena, and Sivaram Pillarisetti

From the Reddy US Therapeutics, Dr. Reddy's Laboratories, Norcross, Georgia 30071 and Department of Medicine, Columbia University, New York, New York 10032

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with a broad array of cellular targets, such as cytoskeletal proteins and transcription factors. Recent studies with GSK-3-null mice showed impaired NFB-mediated survival responses. Because NFB serves a dual role as a key regulator of cytokine-induced inflammatory gene expression and apoptosis, we investigated whether modulation of GSK-3 expression affects cytokine-induced and NFB-mediated inflammatory gene expression. We observed that tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) treatment of primary cultures of human microvascular cells reduced net endogenous active GSK-3 protein levels while inducing inflammatory cytokine (IL-6 and monocyte chemoattractant protein-1 (MCP-1)) expression. Interestingly, inhibition of GSK-3 by antisense oligonucleotides or pharmacological agent (10 mM lithium) potentiated TNF-induced expression of IL-6 and MCP-1 by 2–6-fold suggesting that inhibition of GSK-3 under inflammatory conditions (exposure to TNF- and IL-1) may contribute to enhanced cytokine expression. Overexpression of GSK-3 in endothelial cells, in contrast, significantly inhibited (by 70%, p < 0.01) both TNF- and IL-1-induced expression of IL-6, MCP-1, and vascular cell adhesion molecule-1. Using adenoviruses in lipopolysaccharide-stimulated mice, overexpression of GSK-3 significantly decreased TNF- expression in lung and heart tissues (38 and 15%, respectively), further confirming the anti-inflammatory role of GSK-3. Overexpression of GSK-3 did not affect the TNF--induced nuclear translocation of NFB but reduced the nuclear half-life of TNF--induced NFB considerably (by as much as 9 h) and enhanced phosphorylation (by as much as 33%). Interestingly, neither endothelial cell survival nor NFB-mediated expression of anti-apoptotic genes was affected by GSK-3 overexpression. We conclude that GSK-3 selectively regulates NFB-mediated inflammatory gene expression by controlling the flow of NFB activity between transcription of inflammatory and survival genes.

Received for publication, March 15, 2006

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ To whom correspondence should be addressed: Reddy US Therapeutics, Dr. Reddy's Laboratories, 3065 Northwoods Circle, Norcross, GA 30071. Tel.: 770-446-9500; Fax: 770-446-1950; E-mail: avines{at}reddyus.com.

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