Traumatic injury to the central nervous system initiates inflammatory processes such as the synthesis of proinflammatory mediators that contribute to secondary tissue damage. Hence, administration of anti-inflammatory cytokines, such as interleukin-10 (IL-10) may be neuroprotective. Moderate hypothermia (30-32 degrees C) also decreases the pro-inflammatory response to traumatic brain injury (TBI). Thus, we hypothesized that the combination of IL-10 and hypothermia would provide synergistic neuroprotective effects after TBI. To test this hypothesis, fifty isoflurane-anesthetized rats underwent a controlled cortical impact (2.7 mm tissue deformation at 4 m/s) or sham injury and then were randomly assigned to one of five conditions (TBI/VEH Normothermia (37 degrees C), TBI/VEH Hypothermia (32 degrees C for 3 h), TBI/IL-10 Normothermia, TBI/IL-10 Hypothermia, and Sham/VEH Normothermia). Human IL-10 (5 microg) or VEH was administered (i.p.) 30 min after surgery. Function was assessed by established motor and cognitive tests on post-operative days 1-5 and 14-18, respectively. Cortical lesion volume and hippocampal CA(1)/CA(3) cell survival were quantified at 4 weeks. Brain sections from 15 additional rats were immunohistochemically assessed (MoAB RP-3) to determine neutrophil accumulation at 5 h after TBI. The administration of IL-10 after TBI produced an approximately 75% reduction in the number of RP-3-positive cells in both the normothermic and hypothermic groups vs. the normothermic vehicle-treated group (P<0.05), but did not improve functional outcome. In contrast, hypothermia alone enhanced both motor and cognitive function and increased CA(3) neuronal survival after TBI. Contrary to our hypothesis, systemic administration of IL-10 combined with hypothermia did not provide synergistic neuroprotective effects after TBI. Rather, IL-10 administration suppressed the beneficial effects produced by hypothermia alone after TBI. The mechanism(s) for the negative effects of IL-10 combined with hypothermia after TBI remain to be determined.