title: Synergistic cooperation between methamphetamine and HIV-1 gsp120 through the P13K/Akt pathway induces IL-6 but not IL-8 expression in astrocytes.
abstract: HIV-1 envelope protein gp120 has been extensively studied for neurotoxic effects that have been attributed to the increased expression of various proinflammatory cytokines in the CNS. Recently we have shown that methamphetamine (MA) also increases expression of proinflammatory cytokines in astrocytes. However, combined effect of gp120 and MA is not known. The present study was undertaken to determine cumulative effect and the mechanism(s)/pathways involved in the functional interaction between gp120 and MA in SVGA astrocytes. Our results clearly suggest that gp120 and MA affect IL-6 but not IL-8 in a synergistic manner and this synergy was mediated by PI3K/Akt and NF-κB pathways. Inhibition of either of these pathways could abrogate the increased expression of IL-6 due to MA or gp120 alone, as well as the increased expression of IL-6 when the astrocytes were treated with both gp120 and MA. These results were confirmed by both, using chemical inhibitors/siRNA as well as western blotting. This study therefore provides novel information regarding the interaction between MA and gp120 in terms of the expression of IL-6 and the mechanisms underlying potential synergy between MA and gp120 in astrocytes.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Shah
authors.forename: Peter S
authors.initials: PS
authors.lastname: Silverstein
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Dhirendra P
authors.initials: DP
authors.lastname: Singh
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008694:Methamphetamine / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D015699:HIV Envelope Protein gp120; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C514793:gp120 protein, Human immunodeficiency virus 1; D008694:Methamphetamine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases