59. A role for high mobility group box-1 protein as an endogenous inflammatory mediator in the rat brain

Abstract

Recently, a role for the alarmin high mobility group box-1 protein (HMGB-1) has been proposed as a late mediator of experimental sepsis. Here, we aimed to further elucidate its role as an endogenous inflammatory mediator in the brain. Rats received an intraperitoneal injection of a septic-like dose of lipopolysaccharide (LPS, 10 mg/kg) and HMGB-1-mRNA-expression and -release was measured in the brain and periphery by RT-PCR, immunohistochemistry and ELISA. Moreover, we investigated the inflammatory potential and the direct action of HMGB-1 on brain cells in primary neuroglial cell cultures of the area postrema and the hypothalamic paraventricular nucleus, brain structures known to be involved in inflammatory signal-processing. We observed an increase of HMGB-1 in serum samples 8 and 24 h after injection with LPS, compared to PBS-injected controls. In hypothalamic tissue, we found HMGB-1-mRNA levels to be basal after LPS injection but immunohistochemical analyses revealed that nuclear hypothalamic HMGB-1-signals decreased and cytoplasmatic signals occurred (24 h), suggesting its local release. In vitro , neuroglial-cells were directly activated by recombinant (r) HMGB-1, as shown by increases of intracellular Ca2+-concentration (calcium-imaging), nuclear factor kappaB translocation and induction of cytokines. Overall, our results substantiate the hypothesis that HMGB-1, released locally within the brain or derived from the circulation, is involved in signaling processes in the brain during LPS-induced inflammation via direct action on brain cells and induction of inflammatory mediators including cytokines.