To test this hypothesis, mice were treated with lithium because it is the only GSK3 inhibitor that selleck is well established to be effective in the CNS after peripheral administration. In mice treated with lithium, the serum IL 6 level 18 hr after LPS administration was 67% lower than in mice not given lithium. This matches a previous report that the GSK3 inhibitor Inhibitors,Modulators,Libraries SB216763 greatly reduced serum IL 6 after LPS challenge. IL 6 levels were elevated in the cerebral cortex and cerebellum, but not hippocampus 18 hr after LPS administra tion, and lithium pretreatment reduced these increases in IL 6. In mice pretreated with lithium, there was also a sig nificant reduction in the activating Inhibitors,Modulators,Libraries tyrosine phosphoryla tion of STAT3 Inhibitors,Modulators,Libraries following LPS administration in the cerebral cortex, hippocampus, and cerebellum.

Inhibitors,Modulators,Libraries Furthermore, inhibition of GSK3 with lithium also reduced the activation of astrocytes, as measured by the astrocyte marker GFAP immunoreactivity, following LPS treatment. Inhibitors,Modulators,Libraries Since STAT3 promotes GFAP expression, this indicates that lithiums inhibition of IL 6 production and STAT3 activation reduces expression of STAT3 dependent astrocyte specific genes such as GFAP, resulting in reduction of astrogliosis induced by LPS. Discussion The inflammatory response mounted in the brain in response to many types of insults is crucial to control and counteract detrimental effects of the insults on neurons. However, neuroinflammation that is severe or chronic can itself damage neurons due to excessive production of cytokines and other inflammatory molecules by astrocytes and microglia.

Therefore, identification of mech anisms capable of controlling selleck chemicals Idelalisib neuroinflammation pro vide avenues to interrupt the inflammatory process to prevent its deleterious consequences. Here, we identify novel cooperative actions of STAT3 and GSK3 that control IL 6 production by glia during sepsis induced neuroin flammation. The production of IL 6 by glia was largely blocked by interventions inhibiting the activity of STAT3 or GSK3, revealing the strong dependence of IL 6 pro duction in glia on these signaling molecules. Sepsis caused a large increase in IL 6 in the serum, some of which likely accounted for the increased brain levels of IL 6. However, IL 6 also is produced locally in the brain since its level increased after centrally administered LPS and it was produced by LPS stimulated primary astrocytes and microglia in culture. IL 6 in the brain is apparently a dual edged sword, having both beneficial effects but also deleterious effects, likely depending on the magni tude and duration of its stimulated production.