title: Cigarette smoke-induced CXCR3 receptor up-regulation mediates endothelial apoptosis.
abstract: Endothelial monocyte-activating polypeptide II (EMAP II) and interferon-inducible protein (IP)-10 are proinflammatory mediators, which in addition to their chemokine activities, selectively induce apoptosis in endothelial cells and are up-regulated in the lungs of cigarette smoke-exposed humans. Previously, we showed that EMAP II is an essential mediator of cigarette smoke-induced lung emphysema in mice linking endothelial cell apoptosis with inflammation. Here we addressed the role of the CXCR3 receptor in EMAP II-induced and IP-10-induced apoptosis in endothelial cells and its regulation by cigarette smoke. We found that both neutralizing antibodies and small inhibitory RNA to CXCR3 abrogated EMAP II-induced and IP-10-induced endothelial caspase-3 activation and DNA fragmentation. CXCR3 receptor surface expression in human lung microvascular endothelial cells and in lung tissue endothelium was up-regulated by exposure to cigarette smoke. In tissue culture conditions, EMAP II-induced and IP-10-induced apoptosis was enhanced by preincubation with cigarette smoke extract. Interestingly, serum starvation also induced CXCR3 up-regulation and enhanced EMAP II-induced endothelial apoptosis. Signal transduction via p38 mitogen-activated protein kinase activation was essential for CXCR3-induced cell death, but not for CXCR3 receptor up-regulation by cigarette smoke. In turn, protein nitration was required for CXCR3 receptor up-regulation by cigarette smoke and consequently for subsequent CXCR3-induced cell death. In conclusion, the concerted up-regulation of proinflammatory EMAP II, IP-10, and CXCR3 by cigarette smoke could sustain a cascade of cell death that may promote the alveolar tissue loss noted in human emphysema.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Linden A
authors.initials: LA
authors.lastname: Green
authors.forename: Daniela
authors.initials: D
authors.lastname: Petrusca
authors.forename: Gangaraju
authors.initials: G
authors.lastname: Rajashekhar
authors.forename: Tom
authors.initials: T
authors.lastname: Gianaris
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Schweitzer
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Justice
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Matthias
authors.initials: M
authors.lastname: Clauss
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology; D009363:Neoplasm Proteins / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D012906:Smoke; D014026:Nicotiana / Q000737:chemistry*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D016895:Culture Media, Serum-Free; D016207:Cytokines; D009363:Neoplasm Proteins; D010936:Plant Extracts; D016601:RNA-Binding Proteins; D054367:Receptors, CXCR3; D012906:Smoke; C077219:small inducible cytokine subfamily E, member 1; C002744:3-nitrotyrosine; D014443:Tyrosine