Astrocytes can either exacerbate or ameliorate secondary degeneration at sites of injury in the CNS but the contextual basis for eliciting these opposing phenotypes is poorly understood. In this study, we demonstrate that the two major cytokines produced by Th1 and Th2 cells, interferon-gamma (IFN-gamma), and interleukin-4 (IL-4), respectively, contribute differentially to shaping a neuroprotective response in astrocytes. While IFN-gamma protects the ability of oxidatively stressed murine astrocytes to clear extracellular glutamate in culture, IL-4 has no effect at any concentration that was tested (10-100 ng/mL). The enhanced release of neuroprotective thiols and lactate by astrocytes in response to T cell stimulation is mimicked by both IL-4 and IFN-gamma. When co-administered, IL-4 abrogated the protective effect of low IFN-gamma on the glutamate clearance function of oxidatively stressed astrocytes in a dose-dependent manner. Astrocyte-conditioned media obtained from cells cultured in the presence of IL-4 (10 or 100 ng/mL) or IFN-gamma (10 ng/mL) decreased by approximately 2-fold, neuronal apoptosis induced by oxidative stress in vitro. However, unlike IL-4, IFN-gamma at high concentrations (100 ng/mL) was not neuroprotective. Our studies with IFN-gamma and IL-4 suggest that a balanced Th1 and Th2 cytokine response might be needed for protecting two key astrocytic functions, glutamate clearance and thiol secretion and might be pertinent to neuroprotective approaches that are aimed at inhibition of an initial pro-inflammatory response to injury or its sustained boosting.