Meanwhile, we observed that paroxetine reduced BV2 microglia mediated neurotoxi

Vitronectin activation of vB3 integrin in astrocytes signals through PKC and RhoA, downstream of FAK. However, these molecules probably do not repress CNTF as vB3 integrin does not either. Therefore, the JNK pathway may specifically repress CNTF, perhaps mediating the effects of vitronectin through vB5 17-AAG 臨床試験 but not vB3 integrin. The transcription factor Sox10 is a potent positive regu lator of CNTF gene transcription in Schwann cells. However, in the CNS, Sox10 is specific to oligodendro cytes and is not induced in reactive astrocytes. It remains to be determined whether other Sox family mem bers regulate CNTF in astrocytes. In cultured astrocytes, the CNTF promoter is also accessible to Peroxisome Proliferator Activated Receptor gamma in asso ciation with cAMP Response Element Binding and Activating Transcription Factor 2.<br><br> In duction of CNTF by these transcription factors was dependent upon nitric oxide mediated p38 MAPK activity. We propose that the gp130 JAK STAT3 pathway is an additional pathway activating CNTF transcription in as and plasticity. FAK is largely unphosphorylated in the adult brain and activated pFAK immunostaining ap pears highest in neurons. Thus, astroglial FAK 17-DMAG 溶解度 may be more responsive to inhibitors than neurons perhaps explaining why the FAK treated mice did not have obvious behavioral changes. Clinical trials for cancer with FAK inhibitors which reach the CNS suggest that they are well tolerated. Even so, it will be important to define the effects of chronic treatment with FAK inhibition on CNS function.<br><br> trocytes, but that the FAK pathway chronically inhibits STAT3 at the Ser 727 residue, providing new insight into co regulation by integrins and cytokine recep tors. FAK inhibition A66 構造 robustly induced CNTF while causing a large reduction in pJNK and pSTAT3, reveal ing a novel integrin STAT3 link. JNK can phosphorylate STAT3 at this inhibitory site and pSTAT3 can have reduced transcriptional activity. In appar ent contrast, pSTAT3 can cause stable STAT3 STAT3 DNA binding activity. It is possible that pSTAT3 has gene specific interactions similar to methyl CpG binding protein 2 which can inhibit or activate transcription when associated with other tran scription factors. In astrocytes, CNTF induces phos phorylation of STAT3 at Tyr 705 for transcriptional activity in vitro and in vivo.<br><br> C6 glioma cells reportedly do not express the CNTF alpha receptor but can respond to CNTF, possibly through the IL 6 receptor to activate JAK STAT3 signaling as shown in BaF3 cells. In our hands, CNTF along with LIF only slightly activated STAT3 in C6 cells, whereas IL 6 had robust effects. This suggests that the gp130 receptor and not the LIFBR required for LIF binding, is mainly involved in regulating CNTF. The role of STAT3 is also consistent with our finding that IL 6 and CNTF increase CNTF expression in astrocytes of the adult brain and that STAT3 binds the CNTF pro moter. This feed forward autoregulation by CNTF is present in the retina and in astrocyte and C6 astroglioma cell cultures. Despite the robust activation of STAT3 by IL 6 in C6 cells the increase in CNTF mRNA was only 10%.