Cytokines and HIV envelope glycoprotein gp120 stimulate Na+/H+ exchange in astrocytes

The pathogenesis of the human immunodeficiency virus (HIV)-associated cognitive/motor complex, or acquired immunodeficiency syndrome (AIDS) dementia complex, is unknown, but it afflicts over 50% of all patients infected with HIV-1. Because neurons are not directly infected with HIV-1, the causes of neuronal dysfunction are undoubtedly indirect. We investigated the role of the astrocyte in the development of AIDS dementia complex, focusing on cytokine and HIV-1 gp120 stimulation of Na+/H+ exchange (NHE) activity of primary rat astrocytes. Our results show that the cytokines tumor necrosis factor-alpha, interferon (IFN)-gamma, and interleukin (IL)-1 beta (all found to be elevated in the central nervous system of AIDS patients), can stimulate Na+/H+ exchange, but that transforming growth factor-beta, IL-2, and IL-6 do not. IFN-gamma and gp120-induced activation of Na+/H+ exchange appears to be mediated through activation of tyrosine kinase (TK), because TK inhibitors block the action of IFN-gamma and gp120. Additionally, gp120 induces tyrosine phosphorylation of two proteins (approximately 90 and 130 kDa), which is also inhibited by TK inhibitors. The predominant NHE isoform present in rat astrocytes is NHE-1; however, other isoforms are also present. We conclude that Na+/H+ exchange of rat astrocytes can be differentially stimulated by cytokines and HIV-1 gp120. We hypothesize that the resultant increase in intracellular pH with its concomitant changes in astrocyte membrane permeability properties produces an imbalance in the K+ and glutamate microenvironment of the neurons, leading to a rise in intraneuronal Ca2+ and eventual neuronal dysfunction and/or demise.