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

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 LPSinduced expression of inducible nitric-oxide synthase. TGase 2 activates NFB via a novel pathway. Rather than stimulating phosphorylation and degradation of the inhibitory subunit of NFB (IB ), TGase2 induces its polymerization. This polymerization results in dissociation of NFB 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 IB in the cytosol of cells overexpressing TGase 2. In an LPS-induced rat brain injury model, TGase inhibitors significantly reduced TNFsynthesis. The findings are consistent with a model in which LPS-induced NFB activation is the result of phosphorylation of IB by IB kinase as well as IB polymerization by TGase 2. Safe and stable TGase2 inhibitors may be effective agents in diseases associated with inflammation.