However, chronic or high increases in IL 6 levels in the brain lead to neuronal and cognitive selleck chemicals llc impair ments. The actions of IL 6 are partly mediated by its effects on glia, but it also is not clear if the effects of IL 6 on astrocytes and microglia are beneficial or detrimental. IL 6 is considered an important inducer of astrogliosis, promoting reactive responses regulating the activation state of astrocytes, but chronic or excessive activa tion of glia is often associated with neuronal loss and may contribute to many widespread neurodegenerative dis eases, such as Alzheimers disease and multiple sclerosis. Our findings indicate that inhibition of STAT3 and GSK3 provide mechanisms to intervene to reduce IL 6 produc tion.

Inhibitors,Modulators,Libraries In glia, IL 6 production was highly dependent on the transcription factor STAT3, suggesting that by activating STAT3 IL 6 promoted its own production, as well as acti vating astrocytes as indicated by increases Inhibitors,Modulators,Libraries in the astrocyte reactive marker GFAP. This amplification loop was recently identified in B cells, as B cell lymphoma with high expression of STAT3 exhibited elevated production of IL 6. Our study expands this observation by show ing this Inhibitors,Modulators,Libraries mechanism of a feed forward loop is activated in the brain after sepsis. Thus, this may provide a target to specifically dampen the effects of IL 6 on glia after sepsis. GSK3 also was required for IL 6 production, as inhibitors of GSK3 greatly attenuated IL 6 production. Although other cytokines and chemokines also were regulated by GSK3 inhibitors, IL 6 displayed the greatest dependence on GSK3.

These findings likely signify cooperative actions of STAT3 and GSK3 in promoting IL 6 production since STAT3 activation is dependent on GSK3. Thus, GSK3 is capable of promoting IL 6 production by contributing to the activation of both STAT3 and NF ?B. Inhibitors,Modulators,Libraries Conclusion The identification of GSK3 as a regulator of IL 6 produc tion in the brain expands the already well known role of GSK3 as an integrator of many signaling pathways involved in inflammatory signaling and indicates that inhibition of GSK3 may provide a new therapeutic strategy to counteract the detrimental consequences of sepsis in the brain. Furthermore, in contrast to interven tions targeting individual transcription factors, inhibiting GSK3 enables simultaneous regulation of multiple tran scription factors involved in inflammatory signaling, a therapeutic potential strengthened by the rapidly growing armament of GSK3 inhibitors that includes lithium, a drug already used therapeutically in human patients.

These agents may contribute Inhibitors,Modulators,Libraries to the regulation of inflam mation, which continues to be a pressing problem because of the widespread association of excessive selleck kinase inhibitor inflam mation with many diseases, and particularly neuroinflam mation, which contributes to a broad range of neurodegenerative diseases.