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)-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.
Highlights
Transglutaminase 2 (TGase 2; E.C. 2.3.2.13, protein-glutamine ␥-glutamyltransferase)1 belongs to a family of Ca2ϩ-dependent enzymes that catalyzes N⑀-(␥-L-glutamyl)-L-lysine isopeptide bond formation between peptide bound lysine and glutamine residues [1]
We observed that transient transfection of TGase 2 in the BV-2 microglia increases nuclear factor (NF)-B activity [30]. inducible nitric-oxide synthase (iNOS) is triggered by NF-B activation
We showed that an increase of TGase activity is associated with NF-B activation via an IKK-independent pathway in microglia and SH-SY5Y cells
Summary
Transglutaminase 2 (TGase 2; E.C. 2.3.2.13, protein-glutamine ␥-glutamyltransferase) belongs to a family of Ca2ϩ-dependent enzymes that catalyzes N⑀-(␥-L-glutamyl)-L-lysine isopeptide bond formation between peptide bound lysine and glutamine residues [1]. TGase 2 has been detected in the synovial fluid of patients with arthritis [15] and in the serum and cerebral spinal fluid of patients with amyotrophic lateral sclerosis [16] These reports suggest that the inappropriate expression and/or presentation of TGase 2 to T cells might contribute to these diseases in genetically predisposed individuals. Multiple factors must contribute to the activation of TGase 2 in oxidative stress and in the elevation of intracellular calcium This suggests that induced-TGase 2 in the activated astroglial cells may participate in the pathogenesis of neurodegenerative diseases. Neurodegenerative diseases, such as Parkinson’s disease [23, 24] and Alzheimer’s disease [25, 26], and neuro-AIDS brains [22] are closely associated with increased brain TGase 2 expression. We tested whether TGase inhibition might be effective at reducing NF-B activation in the LPS-induced rat brain injury model
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