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.

HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

“…IL-6 has been involved in the induction of semimature DCs endowed with tolerogenic properties (25), and its induction by gp120 has been shown in some cell models (26)(27)(28)(29)(30). Recently, HIV-1-induced IL-6 has been reported to contribute to myeloid-derived suppressor cell (MDSC) expansion (31).…”

The HIV-1 transgenic rat model of neuroHIV

“…In addition to its apoptotic effects, gp120 induces activation of the inflammatory cytokines, IL-1β, TNF-α, IL-6, IL-8, and CCL5, in rats and humans (Ronaldson 2006; Shah 2010; Shah, Singh et al 2011; Shah 2011). The impact of gp120 on brain function was demonstrated by experiments using the exogenous administration of gp120 to rodents and the expression of shedable gp120 in transgenic mice.…”

HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability

“…The blood-retinal barrier has a similar nature to the BBB and is derived from the same embryonic primordium. Exposure of neurons to HIV gp120 glycoprotein can increase oxidative stress and promote production of inflammatory cytokines, and increased expression of pro-inflammatory cytokines, including IL-6, IL-8, and CCL5, was observed in astrocytes upon exposure to gp120 glycoprotein (52)(53)(54). Exposure to gp120 results in increased oxidative stress in astrocytes, including decreased GSH/GSSG ratios and reduced levels of glutathione peroxidase and glutathione reductase (51).…”