In this study, treatment with ETs stimulated the production and release of CCL2 and CXCL1 in cultured astrocytes. The ef fect of ET receptor agonist and antagonists showed that the actions of ET 1 were mediated by ETB receptors. From these findings, activation of astrocytic ETB receptors is thought to stimulate CCL2 and CXCL1 production Tofacitinib manufacturer directly. Increased production of astrocytic CCL2 and CXCL1 was observed in nerve tis sue damaged by brain ischemia and neurodegenerative diseases. Brain ETs have been shown to be in creased in several brain pathologies and regulate several pathophysiological responses of astrocytes, including the production of extracellular signaling molecules, through ETB receptors. Thus, the ET induced chemokine production in cultured astrocytes suggests that ETs are one of the factors to stimulate CCL2 and CXCL1 pro duction at the damaged nerve area.

ETs decrease astrocytic CX3CL1 production Differing from CCL2 and CXCL1, production of astro cytic CX3CL1 decreased following treatment with ETs, which was also mediated by ETB re ceptors. CX3CL1 is relatively Inhibitors,Modulators,Libraries abundant in the brain, where sub populations of neurons constitu tively express the protein. Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries We found that cultured as trocytes had a comparably high level of CX3CL1 when compared to cerebral neurons. As for the regu lation of astrocytic CX3CL1, pro inflammatory cyto kines, such as tumor necrosis factor alpha and IFN, stimulate its production in cultured astrocytes. On the other hand, a negative regulatory mechan ism of constitutive CX3CL1 production was suggested by the finding that basal CX3CL1 production in human astrocytomas was reduced by tumor growth factor beta.

The effects of ETs on CX3CL1 production indicate an involvement of ETB receptors in the negative regulation of astrocytic CX3CL1 production. Recently, Donnelly et al. showed that expression of CX3CL1 decreased after spinal cord injury Inhibitors,Modulators,Libraries in mice, al though its cellular sources were not identified. Thus, the negative regulation of astrocytic CX3CL1 by ETs may re flect the reduced CX3CL1 expression in damaged nerve tissues. Signal transduction mechanisms mediating the ET induced chemokine production Activation of astrocytic ETB receptors stimulates several intracellular signal pathways, including PKC, intracellu lar Ca2, and MAP kinases.

The effects of ET 1 on astro cytic chemokine production were significant at 10 to 100 nM, which concentrations of ET 1 acti vated signal mechanisms mediated by PKC, Ca2 and MAP kinases. The effects of signal transduction Inhibitors,Modulators,Libraries inhibitors showed that different mechanisms mediate ETB receptor signals to regulate astrocytic chemokine expression. In addition to the regulation of gene transcription, expression levels of CCL2, CXCL1 and CX3CL1 mRNA can be regulated by alteration of their stabilities. The effect of ET 1 on CCL2 and CXCL1 mRNA expression was inhibited by actinomycin selleck chemicals Bortezomib D.