Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) has profound depressive effects on behavior that are mediated by the inducible expression of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF), in the brain. To assess the regulatory effects of the anti-inflammatory cytokine IL-4 on LPS-induced sickness behavior, rats injected intra-peritoneally (i.p.) with LPS were administered intracerebroventricularly (i.c.v.) with IL-4. IL-4 (30 and 300 ng) potentiated the behavioral effects of LPS (175 microg/1000 g) when both molecules were co-injected. However, when IL-4 (30 ng) was injected 12 h prior to LPS, it blocked the depressing effects of LPS on social exploration. These results indicate that the regulation of cytokine-induced sickness behavior by IL-4 can be either inhibitory or stimulatory depending on the sequencing of IL-4 and LPS treatments.