The pro-inflammatory cytokine interleukin-1 (IL-1) is strongly expressed during brain injury and is able to induce severe cellular brain damage via the production of soluble factors. Different processes regulate IL-1 biological activities, like the production of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). In this report, we describe the sequential effects of IL-4 and IL-10 on the production of interleukin-6 (IL-6) induced by IL-1 in mouse primary astrocytes and compare these effects to those of the synthetic glucocorticoid agonist, dexamethasone. IL-6 secretion and IL-6 mRNA expression were determined by ELISA assay and a comparative RT-PCR method, respectively. Incubation of mouse astrocytes in primary culture simultaneously with IL-1 (10 ng/ml) ϩ IL-10 (10 ng/ml) or IL-1 ϩ dexamethasone (10 Ϫ6 M) markedly reduced IL-1 induced IL-6 secretion and IL-6 mRNA expression, respectively, whereas simultaneous addition of IL-4 (10 ng/ml) did not alter the induction of IL-6 by IL-1. In contrast, after 24 h of IL-1 treatment, the level of IL-6 was decreased below constitutive levels, and this change was reversed by addition of IL-4. IL-6 production in IL-1 pretreated cells was also increased by addition of IL-4, whereas IL-10 and dexamethasone had no effects. The delayed time dependent effect of IL-4 might be partially explained by the induction of IL-4 receptor ␣-chain mRNA expression by IL-1. Therefore, we conclude that IL-10 and dexamethasone have rapid immunosuppressive effects on the astrocyte response to IL-1 stimulation, whereas IL-4, which has a delayed action, acts as an immune inducer.