This is supported by diminished neuroinflammation induced by spinal cord injury after infusion of a monoclonal antibody against IL 6 receptor. Furthermore, the potency of drugs to inhibit IL 6 expression in vitro and in vivo correlates with selleck chemicals their Inhibitors,Modulators,Libraries anti neuroinflammatory and neuroprotective properties. Astrocytes, the main glial cell type of the brain, respond in general to multiple kinds of acute and chronic brain insults with a reaction known as astrogliosis. This reactive astrogliosis involves morphological, structural and biochemical features including thickened cellular pro cesses, increased expression of glial fibrillary protein and the induction of pro inflammatory cytokines including IL 6. Different types of signaling molecules are able to trigger the astrocytic IL 6 mRNA expression via distinct intracellular signaling pathways.

For example, lipopolysaccharide activates the IL 1 receptor asso ciated kinase dependent pathway including I B kinase and nuclear factor B. Another potent group of IL Inhibitors,Modulators,Libraries 6 inducers are cytokines such as tumor necro sis factor a, interleukin 1b, oncostatin M and leu kaemia inhibitory factor. Interestingly, OSM and LIF belong together with IL 6 to the same cytokine family. These IL 6 type cytokines are characterized Inhibitors,Modulators,Libraries by using of glycoprotein gp130 to induce gene expression via Inhibitors,Modulators,Libraries JAK STAT and MAPK cascades Inhibitors,Modulators,Libraries in a NF B dependent manner. Thus, blocking of such pathological IL 6 driven gene expression by low molecular weight inhibitors provides a possible strategy for targeting the onset or further propa gation of astrogliosis and, subsequently, secondary neuro nal cell death.

In the present study, the time and dose dependent stimulation of IL 6 expression by OSM was character AZD2281 ized in human U343 glioma cells. Subsequently, our compound libraries were screened for inhibitory effects on OSM induced IL 6 expression. We identified bioac tive compounds belonging to the chemical class of het eroarylketones. These HAK compounds were able to suppress the LPS induced IL 6 expression in primary mouse and rat astrocytes as well as in an acute septic shock mouse model in vivo. Finally, the underly ing molecular mechanism of HAK compounds interfer ing with key signaling molecules of OSM induced signal transduction cascade was analyzed. We demonstrate a selective suppression by HAK compounds of the OSM mediated phosphorylation of STAT3 at serine 727, which affects STAT3 binding to the NF B subunit p65. Methods Primary cultures of murine astrocytes According to L?ffler, astrocyte rich primary cell cultures were started with brains of newborn mice and rats and were maintained in Dulbeccos modified Eagles medium for 33 days at 37 C in a humified atmosphere with 95% air 5% CO2.