Transglutaminase 2 induces nuclear factor-κB activation via a novel pathway in BV-2 microglia

Abstract

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