title: HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3.
abstract: Chronic lung diseases, such as pulmonary emphysema, are increasingly recognized complications of infection with the human immunodeficiency virus (HIV). Emphysema in HIV may occur independent of cigarette smoking, via mechanisms that are poorly understood but may involve lung endothelial cell apoptosis induced by the HIV envelope protein gp120. Recently, we have demonstrated that lung endothelial apoptosis is an important contributor to the development of experimental emphysema, via upregulation of the proinflammatory cytokine endothelial monocyte-activating polypeptide II (EMAP II) in the lung. Here we investigated the role of EMAP II and its receptor, CXCR3, in gp120-induced lung endothelial cell apoptosis. We could demonstrate that gp120 induces a rapid and robust increase in cell surface expression of EMAP II and its receptor CXCR3. This surface expression occurred via a mechanism involving gp120 signaling through its CXCR4 receptor and p38 MAPK activation. Both EMAP II and CXCR3 were essentially required for gp120-induced apoptosis and exposures to low gp120 concentrations enhanced the susceptibility of endothelial cells to undergo apoptosis when exposed to soluble cigarette smoke extract. These data indicate a novel mechanism by which HIV infection causes endothelial cell loss involved in lung emphysema formation, independent but potentially synergistic with smoking, and suggest therapeutic targets for emphysema prevention and/or treatment.
authors: Indiana University School of Medicine, Cellular and Integrative Physiology, Indianapolis, IN 46202. MClauss@iupui.edu.
authors: Linden A
authors: LA
authors: Green
authors: Ru
authors: R
authors: Yi
authors: Daniela
authors: D
authors: Petrusca
authors: Ting
authors: T
authors: Wang
authors: Alhasan
authors: A
authors: Elghouche
authors: Samir K
authors: SK
authors: Gupta
authors: Irina
authors: I
authors: Petrache
authors: Matthias
authors: M
authors: Clauss
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology* / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D015658:HIV Infections / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000098:blood supply; D055806:Microvessels / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016601:RNA-Binding Proteins / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C515187:CXCR3 protein, human; C527276:CXCR4 protein, human; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; C077219:small inducible cytokine subfamily E, member 1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: HIV; emphysema; endothelium; gp120; lung