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. 2011;6(6):e21261. doi: 10.1371/journal.pone.0021261. Epub 2011 Jun 21.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Astrocytes / cytology
  • Astrocytes / physiology
  • Cell Line
  • Fetus / cytology
  • HIV Envelope Protein gp120 / genetics*
  • HIV Envelope Protein gp120 / metabolism*
  • Humans
  • I-kappa B Proteins / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism*

Substances

  • HIV Envelope Protein gp120
  • I-kappa B Proteins
  • Interleukin-6
  • NF-kappa B
  • NFKBIA protein, human
  • RNA, Small Interfering
  • NF-KappaB Inhibitor alpha