title: HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes.
abstract: The mechanism whereby HIV-infected cells transit from the bloodstream into tissues is not well defined. This phenomenon was addressed by studying the effects of HIV-1 Tat, a protein secreted by infected cells, on human lung microvascular endothelial cells (HMVEC-Ls). It was found that monocyte chemoattractant protein-1 (MCP-1) was released from HMVEC-Ls in a dose- and time-dependent manner after Tat treatment. MCP-1 is a potent beta-chemokine that recruits monocytes and T cells and promotes cell adhesion and transmigration across an endothelial monolayer. It was also observed that MCP-1 and the culture medium from Tat-treated HMVEC-Ls were chemotactic for CD14(+) monocytes from human peripheral blood and for THP-1, a promonocytic cell line used as a model system. To characterize the signaling pathways underlying the observed induction of MCP-1, HMVEC-Ls were treated with 2 different protein kinase inhibitors: PD98059, a MAP kinase inhibitor, and GF109203X, a protein kinase C (PKC) inhibitor. MCP-1 release was significantly reduced when PKC was inhibited, and slightly decreased when PI3 kinase was blocked; no effect on MCP-1 release was observed on MAP kinase inhibition. Similarly, transmigration of THP-1 cells was significantly impaired by the PKC inhibitor, but not by the other tested inhibitors. These data indicate that the HIV-1 Tat protein may act as a protocytokine by causing the release of MCP-1 from the endothelial monolayer, and thereby facilitating monocyte transmigration into tissues via a PKC signaling pathway.
authors.affiliation: Division of Experimental Medicine and Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA.
authors.forename: I W
authors.initials: IW
authors.lastname: Park
authors.forename: J F
authors.initials: JF
authors.lastname: Wang
authors.forename: J E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism*; D002633:Chemotaxis; D017077:Culture Media, Conditioned / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015696:Gene Products, tat / Q000494:pharmacology* / Q000502:physiology; D015497:HIV-1 / Q000737:chemistry*; D006801:Humans; D018950:Lipopolysaccharide Receptors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008833:Microcirculation / Q000166:cytology; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D015696:Gene Products, tat; D018950:Lipopolysaccharide Receptors; D017978:Receptors, Growth Factor; D054322:tat Gene Products, Human Immunodeficiency Virus; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D011493:Protein Kinase C