Transglutaminase 2 induces nuclear factor-kappaB 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)-kappaB and thereby enhances LPS-induced expression of inducible nitric-oxide synthase. TGase 2 activates NF-kappaB via a novel pathway. Rather than stimulating phosphorylation and degradation of the inhibitory subunit alpha of NF-kappaB (I-kappaBalpha), TGase2 induces its polymerization. This polymerization results in dissociation of NF-kappaB 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 alpha (TNF-alpha). Indeed, TGase inhibitors prevent depletion of monomeric I-kappaBalpha in the cytosol of cells overexpressing TGase 2. In an LPS-induced rat brain injury model, TGase inhibitors significantly reduced TNF-alpha synthesis. The findings are consistent with a model in which LPS-induced NF-kappaB activation is the result of phosphorylation of I-kappaBalpha by I-kappaB kinase as well as I-kappaBalpha polymerization by TGase 2. Safe and stable TGase2 inhibitors may be effective agents in diseases associated with inflammation.