title: HMGB1 increases permeability of the endothelial cell monolayer via RAGE and Src family tyrosine kinase pathways.
abstract: High-mobility group box 1 (HMGB1) was recently established as a proinflammatory mediator of sepsis, and its potential role in the pathogenesis of sepsis remains elusive. In the present study, we determined whether HMGB1 increases the permeability of the endothelial cell monolayer in sepsis. Permeability was measured from fluorescein isothiocyanate (FITC)-dextran 40-kDa flux across the endothelial cell monolayer at control and after HMGB1 administration. We found that HMGB1 increased human umbilical vein endothelial cell permeability to FITC-dextran 40 kDa in a time- and concentration-dependent manner. HMGB1 induced the mRNA transcription and protein expression of receptor for advanced glycation end products (RAGE). Blockade of cell surface receptors RAGE with specific neutralizing antibodies and RAGE siRNA or blockade of Src family tyrosine kinase with inhibitor PP2 significantly reduced HMGB1-induced hyperpermeability of endothelial cell monolayer. Our data demonstrate that (1) HMGB1 increases permeability of endothelial cell monolayer in a time- and concentration-dependent manner and (2) HMGB1-induced hyperpermeability is mediated through RAGE and Src family tyrosine kinase signaling pathway. These findings may have implications for therapeutic interventions in patients with sepsis.
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, 197 Ruijin 2 Road, 200025, Shanghai, China. huangwenchang12345@163.com
authors.forename: Wenchang
authors.initials: W
authors.lastname: Huang
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Ruyuan
authors.initials: R
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Enqiang
authors.initials: E
authors.lastname: Mao
authors.forename: Yaoqing
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010539:Permeability; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000032:analysis; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D024243:HMGB1 Protein; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D019061:src-Family Kinases