HIV-1 gp120 Induces Expression of IL-6 through a Nuclear Factor-Kappa B-Dependent Mechanism

Suppression by gp120 Specific Small Interfering RNA

Ankit Shah, Ashish S. Verma, Kalpeshkumar H. Patel, Richard Noel, Vanessa Rivera-Amill, Peter S. Silverstein, Suman Chaudhary, Hari K. Bhat, Leonidas Stamatatos, Dhirendra P Singh, Shilpa J Buch, Anil Kumar

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere21261
JournalPloS one
Volume6
Issue number6
DOIs
StatePublished - Jun 24 2011

Fingerprint

NF-kappa B
small interfering RNA
Human immunodeficiency virus 1
interleukin-6
Small Interfering RNA
HIV-1
Interleukin-6
astrocytes
Astrocytes
IKappaB kinase
HIV
transfection
Transfection
Tropics
Virus Internalization
Phosphorylation
Neurologic Manifestations
Viruses
tropics
phosphorylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

HIV-1 gp120 Induces Expression of IL-6 through a Nuclear Factor-Kappa B-Dependent Mechanism : Suppression by gp120 Specific Small Interfering RNA. / Shah, Ankit; Verma, Ashish S.; Patel, Kalpeshkumar H.; Noel, Richard; Rivera-Amill, Vanessa; Silverstein, Peter S.; Chaudhary, Suman; Bhat, Hari K.; Stamatatos, Leonidas; Singh, Dhirendra P; Buch, Shilpa J; Kumar, Anil.

In: PloS one, Vol. 6, No. 6, e21261, 24.06.2011.

Research output: Contribution to journalArticle

Shah, A, Verma, AS, Patel, KH, Noel, R, Rivera-Amill, V, Silverstein, PS, Chaudhary, S, Bhat, HK, Stamatatos, L, Singh, DP, Buch, SJ & Kumar, A 2011, 'HIV-1 gp120 Induces Expression of IL-6 through a Nuclear Factor-Kappa B-Dependent Mechanism: Suppression by gp120 Specific Small Interfering RNA', PloS one, vol. 6, no. 6, e21261. https://doi.org/10.1371/journal.pone.0021261
Shah, Ankit ; Verma, Ashish S. ; Patel, Kalpeshkumar H. ; Noel, Richard ; Rivera-Amill, Vanessa ; Silverstein, Peter S. ; Chaudhary, Suman ; Bhat, Hari K. ; Stamatatos, Leonidas ; Singh, Dhirendra P ; Buch, Shilpa J ; Kumar, Anil. / HIV-1 gp120 Induces Expression of IL-6 through a Nuclear Factor-Kappa B-Dependent Mechanism : Suppression by gp120 Specific Small Interfering RNA. In: PloS one. 2011 ; Vol. 6, No. 6.
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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.",
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