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J. Biol. Chem., Vol. 279, Issue 51, 53725-53735, December 17, 2004

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Transglutaminase 2 Induces Nuclear Factor-B Activation via a Novel Pathway in BV-2 Microglia^*

Jongmin Lee, Yoon-Seong Kim, Dong-Hee Choi, Moon Suk Bang¶, Tai Ryoon Han¶, Tong H. Joh, and Soo-Youl Kim||

From the Department of Neurology and Neuroscience, Weill Medical College of Cornell University and Burke Medical Research Institute, White Plains, New York 10605 and ^¶Department of Rehabilitation Medicine, College of Medicine, Seoul National University, Seoul 110-744, Republic of Korea

Transglutaminase 2 (TGase 2) expression is increased in inflammatory diseases. We demonstrated previously that inhibitors of TGase 2 reduce nitric oxide (NO) generation in a lipopolysaccharide (LPS)-treated microglial cell line. However, the precise mechanism by which TGase 2 promotes inflammation remains unclear. We found that TGase 2 activates the transcriptional activator nuclear factor (NF)-B and thereby enhances LPS-induced expression of inducible nitric-oxide synthase. TGase 2 activates NF-B via a novel pathway. Rather than stimulating phosphorylation and degradation of the inhibitory subunit of NF-B (I-B), TGase2 induces its polymerization. This polymerization results in dissociation of NF-B and its translocation to the nucleus, where it is capable of up-regulating a host of inflammatory genes, including inducible nitric-oxide synthase and tumor necrosis factor (TNF-). Indeed, TGase inhibitors prevent depletion of monomeric I-B in the cytosol of cells overexpressing TGase 2. In an LPS-induced rat brain injury model, TGase inhibitors significantly reduced TNF- synthesis. The findings are consistent with a model in which LPS-induced NF-B activation is the result of phosphorylation of I-B by I-B kinase as well as I-B polymerization by TGase 2. Safe and stable TGase2 inhibitors may be effective agents in diseases associated with inflammation.

Received for publication, July 7, 2004 , and in revised form, October 4, 2004.

^* 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 914-597-2500, ext. 3041; Fax: 914-597-2757; E-mail: tgase{at}hanmail.net.

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