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.
Lee
Jongmin
J
Department of Neurology and Neuroscience, Weill Medical College of Cornell University and Burke Medical Research Institute, White Plains, NY 10605, USA.
Kim
Yoon-Seong
YS
Choi
Dong-Hee
DH
Bang
Moon Suk
MS
Han
Tai Ryoon
TR
Joh
Tong H
TH
Kim
Soo-Youl
SY
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