We refer to the microglial cytokine expression profile changes described here as M1 like or M2 like, fol lowing the Tofacitinib baldness general scheme of M1 and M2 activation phenotypes developed in mouse macrophages and sub sequently adopted to describe microglial activation phe notypes. There are a number of differences between human microglia Inhibitors,Modulators,Libraries and murine microglia. For example, although iNOS is a prototypic marker of M1 activated murine microglia, it is not expressed by human micro glia. In addition, human microglia do not express certain Th1 or Th2 cytokines such as IFNg or IL 4. There might also be additional differences between macrophages and microglia. For these and other rea sons, we refer to the microglial phenotypes described here as M1 like or M2 like. Importantly, we note these changes regardless of the types of immunological stimuli applied.

The observed effects of IRF3 transgene in the suppression of proinflammatory cyto kine genes is novel and points to a mechanism by which IRF3 influences other signaling pathways. In addition, we have obtained novel findings that indicate that the PI3K pathway Inhibitors,Modulators,Libraries plays a predominantly Inhibitors,Modulators,Libraries anti inflammatory role in microglial activation. It played a particularly potent role in the induction of anti inflammatory and immunoregulatory cytokines such as IL 10, IL 1ra and IFNb. These results together suggest that activation of the PI3K Akt pathway in microglia can lead to the resolution of inflammation and promotion of repair under neuroinflammatory con ditions. The PI3K Akt pathway is unique for its multitudes of roles in transcriptional regulation of cytokine genes.

Employing a pharmacological inhibitor, we show that the PI3K Akt pathway is involved in both the suppres sion and the enhancement of cytokine genes in IRF3 transduced Inhibitors,Modulators,Libraries microglia. One might speculate that the impressive amounts of suppres sion of proinflammatory genes in Ad IRF3 transduced cells are at least in part secondary to the induction of anti inflammatory and immunoregulatory genes, as IL 1ra, IL 10 and IFNb each can function as a suppressor of proinflammatory cytokine expression. For example, we have previously shown that recombinant IFNb sup presses IL 1 and increases IL 1ra production in human microglia. IFNb also induces certain chemokines. Microarray analysis of human peripheral blood mononuclear cells exposed to IFNb demon strated that distinct sets of genes are upregulated or downregulated by IFNb, the latter including IL 1b, CXCL1, and IL 8.

Therefore, IFNb most certainly played a role as an intermediary cytokine that mediated the effect Inhibitors,Modulators,Libraries of Ad IRF3 in our system. Additional cyto kines that might have played a role in our system include IFNa, as well as type III IFNs. Type III IFNs are newly discovered interferons that share a number of similarities with type I IFNs including their mechanism of induction and their sellectchem biological activities.