Acute systemic administration of interleukin-10 suppresses the beneficial effects of moderate hypothermia following traumatic brain injury in rats.

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.

Complementary adhesion molecules promote neutrophil-Kupffer cell interaction and the elimination of bacteria taken up by the liver.

Most bacteria that enter the bloodstream are taken up by the liver. Previously, we reported that such organisms are initially bound extracellularly and subsequently killed by immigrating neutrophils, not Kupffer cells as widely presumed in the literature. Rather, the principal functions of Kupffer cells demonstrated herein are to clear bacteria from the peripheral blood and to promote accumulation of bactericidal neutrophils at the principal site of microbial deposition in the liver, i.e., the Kupffer cell surface. In a mouse model of listeriosis, uptake of bacteria by the liver at 10 min postinfection i.v. was reduced from approximately 60% of the inoculum in normal mice to approximately 15% in mice rendered Kupffer cell deficient. Immunocytochemical analysis of liver sections derived from normal animals at 2 h postinfection revealed the massive immigration of neutrophils and their colocalization with Kupffer cells. Photomicrographs of the purified nonparenchymal liver cell population derived from these infected mice demonstrated listeriae inside neutrophils and neutrophils within Kupffer cells. Complementary adhesion molecules promoted the interaction between these two cell populations. Pretreatment of mice with mAbs specific for CD11b/CD18 (type 3 complement receptor) or its counter-receptor, CD54, inhibited the accumulation of neutrophils in the liver and the elimination of listeriae. Complement was not a factor; complement depletion affected neither the clearance of listeriae by Kupffer cells nor the antimicrobial activity expressed by infiltrating neutrophils.

The Th1 versus Th2 cytokine profile in cerebrospinal fluid after severe traumatic brain injury in infants and children.

OBJECTIVE: To further characterize the Th1 (proinflammatory) vs. the Th2 (antiinflammatory) cytokine profile after severe traumatic brain injury (TBI) by quantifying the ventricular cerebrospinal fluid concentrations of Th1 cytokines (interleukin [IL]-2 and IL-12) and Th2 cytokines (IL-6 and IL-12) in infants and children. DESIGN: Retrospective study. SETTING: University children's hospital. PATIENTS: Twenty-four children hospitalized with severe TBI (admission Glasgow Coma Scale score, <13) and 12 controls with negative diagnostic lumbar punctures. INTERVENTIONS: All TBI patients received standard neurointensive care, including the placement of an intraventricular catheter for continuous drainage of cerebrospinal fluid. MEASUREMENTS AND MAIN RESULTS: Ventricular cerebrospinal fluid samples (n = 105) were collected for as long as the catheters were in place (between 4 hrs and 222 hrs after TBI). Cerebrospinal fluid samples were analyzed for IL-2, IL-4, IL-6, and IL-12 concentrations by enzyme-linked immunoassay. Peak and mean IL-6 (335.7 +/- 41.4 pg/mL and 259.5 +/- 37.6 pg/mL, respectively) and IL-12 (11.4 +/- 2.2 pg/mL and 4.3 +/- 0.8 pg/mL, respectively) concentrations were increased (p <.05) in children after TBI vs. controls (2.3 +/- 0.7 pg/mL and 1.0 +/- 0.5 pg/mL) for IL-6 and IL-12, respectively. In contrast, peak and mean IL-2 and IL-4 concentrations were not increased in TBI children vs. controls. Increases in the cerebrospinal fluid concentration of IL-6 were significantly associated with admission Glasgow Coma Scale score of