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.
Department of Neurology and Neuroscience, Weill Medical College of Cornell University and Burke Medical Research Institute, White Plains, NY 10605, USA.
Jongmin
J
Lee
Yoon-Seong
YS
Kim
Dong-Hee
DH
Choi
Moon Suk
MS
Bang
Tai Ryoon
TR
Han
Tong H
TH
Joh
Soo-Youl
SY
Kim
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism*; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation; D011108:Polymers / Q000737:chemistry; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D011503:Transglutaminases / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D009573:Nitrites; D011108:Polymers; C000717609:Tgm2 protein, rat; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins