When both IRF8 and IRF1 were considering overexpressed in OPCs, preapoptotic cells were significantly more than those in the OPCs overexpres sing IRF1 alone, although there was no statistical significance in reduction of live transfected cells between the IRF1 empty and IRF1 IRF8 groups at 24 h after transfection. These results indicated that overexpressed IRF8 protein directly enhances the proapoptotic effects of IRF1 in OPCs even Inhibitors,Modulators,Libraries in the absence of IFNg. Discussion Proapoptotic effects of IFNg and at most minimal cyto toxic effects of IFNb on OPCs have been reported pre viously. In the present study, however, we have directly compared effects of IFNg and IFNb on OPCs in the same in vitro condition, and confirmed a substantial difference in proapoptotic effects between the two IFNs.

Furthermore, IFNb was not protective against IFNg induced OPC apoptosis, despite several prior reports that IFNb antagonizes Inhibitors,Modulators,Libraries IFNg signaling. As far as we could determine by transcriptional induction of IRF1, simultaneous application of IFNb failed to reduce IFNg mediated robust induction of IRF1. Although the mechanisms underlying the beneficial therapeutic effects of IFNb on relapsing remitting MS are still Inhibitors,Modulators,Libraries largely unknown, recent studies have indicated that IFNb and type I IFN receptor mediated signaling limit CNS autoimmunity by regulating innate immune responses in peripheral tissues and the produc tion and properties of TH17 cells, a pathogenic T helper subset largely responsible for CNS autoimmunity.

Despite the beneficial effects of IFNb which is further ensured by far less cytotoxicity of IFNb to OPCs, we observed that IFNb did inhibit Inhibitors,Modulators,Libraries the cell cycle in OPCs, though to a lesser extent than IFNg. It is thus conceiva ble that, as demonstrated by Trebst et al, IFNb attenuates the endogenous capability for remyelination, which is presumably masked by its profound beneficial effects on the immune system. Based on the marked difference in proapoptotic effects between IFNg and IFNb on OPCs, our next aim in this study was to identify those ISGs responsible for IFNg mediated OPC apoptosis. IFNg induces robust and sus tained elevation of IRF1, whereas IFNb elicits only a transient Inhibitors,Modulators,Libraries elevation of IRF1, which ends up being unde tectable at the protein level at 24 h after treatment, indi cating that IRF1 is a candidate for such an ISG. In www.selleckchem.com/products/pazopanib.html support of this, Balabanovs group has recently reported that, using a lentiviral expression system, down regula tion of IRF1 by IRF1 shRNA partially protected against IFNg induced OPC apoptosis, and that forced expres sion of IRF1 reduced the viability of OPCs. We employed a different forced expression system and a dominant negative approach in this study, and con firmed significant involvement of IRF1 in IFNg mediated OPC apoptosis.