title: HIV-1 gp120 induces expression of IL-6 through a nuclear factor-kappa B-dependent mechanism: suppression by gp120 specific small interfering RNA.
abstract: In addition to its role in virus entry, HIV-1 gp120 has also been implicated in HIV-associated neurocognitive disorders. However, the mechanism(s) responsible for gp120-mediated neuroinflammation remain undefined. In view of increased levels of IL-6 in HIV-positive individuals with neurological manifestations, we sought to address whether gp120 is involved in IL-6 over-expression in astrocytes. Transfection of a human astrocyte cell line with a plasmid encoding gp120 resulted in increased expression of IL-6 at the levels of mRNA and protein by 51.3±2.1 and 11.6±2.2 fold respectively; this effect of gp120 on IL-6 expression was also demonstrated using primary human fetal astrocytes. A similar effect on IL-6 expression was observed when primary astrocytes were treated with gp120 protein derived from different strains of X4 and R5 tropic HIV-1. The induction of IL-6 could be abrogated by use of gp120-specific siRNA. Furthermore, this study showed that the NF-κB pathway is involved in gp120-mediated IL-6 over-expression, as IKK-2 and IKKβ inhibitors inhibited IL-6 expression by 56.5% and 60.8%, respectively. These results were also confirmed through the use of NF-κB specific siRNA. We also showed that gp120 could increase the phosphorylation of IκBα. Furthermore, gp120 transfection in the SVGA cells increased translocation of NF-κB from cytoplasm to nucleus. These results demonstrate that HIV-1 gp120-mediated over-expression of IL-6 in astrocytes is one mechanism responsible for neuroinflammation in HIV-infected individuals and this is mediated by the NF-κB pathway.
authors.affiliation: Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, United States of America.
authors.forename: Ankit
authors.initials: A
authors.lastname: Shah
authors.forename: Ashish S
authors.initials: AS
authors.lastname: Verma
authors.forename: Kalpeshkumar H
authors.initials: KH
authors.lastname: Patel
authors.forename: Richard
authors.initials: R
authors.lastname: Noel
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rivera-Amill
authors.forename: Peter S
authors.initials: PS
authors.lastname: Silverstein
authors.forename: Suman
authors.initials: S
authors.lastname: Chaudhary
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.forename: Dhirendra P
authors.initials: DP
authors.lastname: Singh
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D002460:Cell Line; D005333:Fetus / Q000166:cytology; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*
chemical_list: D015699:HIV Envelope Protein gp120; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D034741:RNA, Small Interfering; D000072000:NF-KappaB Inhibitor alpha