title: Pentoxifylline reduces tumor necrosis factor-α and HIV-induced vascular endothelial activation.
abstract: Untreated HIV infection is associated with endothelial dysfunction and subsequent cardiovascular disease, likely due to both direct effects of the virus and to indirect effects of systemic inflammation on the vasculature. We have recently shown that treatment with the antiinflammatory agent pentoxifylline (PTX) improved in vivo endothelial function and reduced circulating levels of the inflammatory markers vascular cell adhesion molecule-1 (VCAM-1) and interferon-gamma-induced protein (IP-10) in HIV-infected patients. To delineate the mechanisms underlying this therapeutic effect, we tested whether clinically relevant concentrations of PTX suppress VCAM-1 or IP-10 release in cultivated human lung microvascular endothelial cells. Indeed, we found that tumor necrosis factor (TNF)-α-induced VCAM-1 was reduced with concentrations of PTX in the low nanomolar range, comparable to plasma levels in PTX-treated groups. We also investigated the effect of HIV proteins and found that HIV transactivator of transcription (HIV-Tat) and HIV-envelope-derived recombinant gp120 enhanced TNF-α-induced VCAM-1 gene expression in lung microvascular and coronary macrovascular endothelial cells, respectively. In addition, PTX and a NF-κB-specific inhibitor reduced this enhanced VCAM-1 gene induction in microvascular and macrovascular endothelial cells. These results provide novel insights in how the antiinflammatory agent PTX can directly reduce HIV-associated proinflammatory endothelial activation, which may underlie vascular dysfunction and coronary vascular diseases.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Linden Ann
authors.initials: LA
authors.lastname: Green
authors.forename: Chul
authors.initials: C
authors.lastname: Kim
authors.forename: Samir K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Gangaraju
authors.initials: G
authors.lastname: Rajashekhar
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
authors.forename: Matthias
authors.initials: M
authors.lastname: Clauss
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D010431:Pentoxifylline