JNK1 2 plays a critical role in induction of CO 2 by ET 1 in endothelial cells. It has been well established that inflammatory responses following e posure to e tracellular stimuli are highly dependent on activation of NF ��B transcription factor, which plays an important role in regulation of several gene e pression. The 5 flanking region of the CO 2 pro moter has been shown to contain several binding sequences for various transcription factors including NF ��B. Therefore, the regulation of CO 2 transcription may be mediated by aberrant activation of several distinct transcrip tion factors dependent on agonists. These reports suggest that NF ��B plays a critical role in the regulation of CO 2 e pression in the development of the inflammatory responses.

Our data showed that ET 1 induced CO 2 gene e pression and PGE2 release was significantly abolished by a selective NF ��B inhibitor Bay11 7082 or NF ��B p65 siRNA, suggesting that NF ��B is involved in ET 1 induced CO 2 e pression in bEnd. 3 cells. Moreover, ET 1 stimulated NF ��B p65 trans location, binding to CO 2 promoter region, and NF ��B transcriptional activity was significantly inhibited by Bay11 7082 and the MAPK inhibitor U0126, SB202190, or SP600125. Drug_discovery Our data further showed that ET 1 stimulated NF ��B transcriptio nal activity was significantly attenuated by blocking Gi and Gq protein coupled ETB receptor dependent pathways, indicating that ET 1 induced activation of NF ��B is mediated through ETB receptor dependent activation of three MAPKs cascades.

These findings are consistent with recent studies indicating that CO 2 e pression and prostacyclin release induced by thrombin were mediated through MAPKs and NF ��B activation in endothelial cells and vascular smooth muscle cells and CO 2 e pression and PGE2 release induced by BK via ERK1 2 link ing to NF ��B activation in astrocytes. The involvement of NF ��B in ET 1 induced CO 2 e pression is also consist ent with previous reports indicating that ET 1 stimulated activation of NF ��B regulates e pression of target genes involved in various CNS inflammatory processes. More over, our recent data have also demonstrated that in bEnd. 3 cells, c Src dependent transactivation of EGFR PI3K Akt and MAPKs linking to c Jun AP 1 cascade is essential for ET 1 induced CO 2 PGE2 upregulation.

We suggest that the findings of these two studies might have a crosstalk in MAPKs and lead to CO 2 e pression induced by ET 1 in these cells. The interplay between these two pathways in the induction of CO 2 will be investigated in the future. Conclusions In this study, we reported here that ET 1 ET receptor system e erts its effects on CO 2 gene e pression and PGE2 release in mouse bEnd. 3 cells. The Gi and Gq protein coupled ETB receptor, ERK1 2, p38 MAPK, JNK1 2, and NF ��B cascades cooperatively mediated these effects of ET 1. These findings concerning ET 1 induced CO 2 PGE2 system imply that ET 1 might play a critical role in brain in jury, vascular inflammation, and CNS d