title: Regulation of endothelial cell inflammation and lung polymorphonuclear lymphocyte infiltration by transglutaminase 2.
abstract: We addressed the role of transglutaminase 2 (TG2), a calcium-dependent enzyme that catalyzes cross-linking of proteins, in the mechanism of endothelial cell (EC) inflammation and lung polymorphonuclear lymphocyte (PMN) infiltration. Exposure of EC to thrombin, a procoagulant and proinflammatory mediator, resulted in activation of the transcription factor nuclear factor κB (NF-κB) and its target genes, vascular cell adhesion molecule 1, monocyte chemotactic protein 1, and interleukin 6. RNAi knockdown of TG2 inhibited these responses. Analysis of NF-κB activation pathway showed that TG2 knockdown was associated with inhibition of thrombin-induced DNA binding as well as serine phosphorylation of RelA/p65, a crucial event that controls transcriptional capacity of the DNA-bound RelA/p65. These results implicate an important role for TG2 in mediating EC inflammation by promoting DNA-binding and transcriptional activity of RelA/p65. Because thrombin is released in high amounts during sepsis, and its concentration is elevated in plasma and lavage fluids of patients with acute respiratory distress syndrome, we determined the in vivo relevance of TG2 in a mouse model of sepsis-induced lung PMN recruitment. A marked reduction in NF-κB activation, adhesion molecule expression, and lung PMN sequestration was observed in TG2 knockout mice compared with wild-type mice exposed to endotoxemia. Together, these results identify TG2 as an important mediator of EC inflammation and lung PMN sequestration associated with intravascular coagulation and sepsis.
authors: Departments of *Pediatrics and †Biomedical Genetics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors: Kaiser M
authors: KM
authors: Bijli
authors: Bryce G
authors: BG
authors: Kanter
authors: Mohammad
authors: M
authors: Minhajuddin
authors: Antony
authors: A
authors: Leonard
authors: Lei
authors: L
authors: Xu
authors: Fabeha
authors: F
authors: Fazal
authors: Arshad
authors: A
authors: Rahman
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology; D019446:Endotoxemia / Q000378:metabolism; D005355:Fibrosis / Q000503:physiopathology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology*; D010766:Phosphorylation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011651:Pulmonary Artery / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D013917:Thrombin; D019204:GTP-Binding Proteins