NF B is also a central Colorectal cancer regulator of microglial responses to activating stimuli, including LPS and cyto kines. In this study, ATL was able to inhibit the LPS evoked degradation of I B a, nuclear translocation of NF B p65 and the DNA binding activities of NF B in BV 2 cells. Previous studies have shown that LXs reduce nuclear translocation of NF B in human neu trophils, mononuclear leukocytes and macrophages. It has also been reported that ATLs reduce NF B mediated Inhibitors,Modulators,Libraries transcriptional activation in an ALX dependent manner, and inhibit the degradation of I B. Therefore, induction of anti inflammatory responses by LXs may be dependent on the NF B sig naling pathway. In addition, LPS also activates MAPK pathways which lead to the induction of another transcription factor, AP 1.

MAPKs are a group of signaling molecules that appear to play key roles in infiammatory processes. We found that phosphorylation of ERK and p38 MAPK in response to LPS is decreased by ATL treatment. Inhibitors,Modulators,Libraries Our results also show that ATL treatment of BV 2 microglia results in decreased DNA binding activities of AP 1 fol lowing LPS stimulation. This observation is Inhibitors,Modulators,Libraries in line with studies in mesangial cells, endothelial cells, neutrophils, fibroblasts and T cells, which have shown that ERK and or p38 MAPK activation is attenuated in the pre sence of LXs. In the present study, ATL failed to inhibit LPS induced phosphorylation of JNK. A previous study in primary astrocytes found that an ATL analogue prevents ATP evoked JNK phosphorylation, but has no effect on TNF a induced JNK phosphoryla tion.

Strikingly, our results show that ATL induces JNK phosphorylation, but has no effect on ERK and p38 MAPK activity. In another study, LXA4 attenuated microvascular fluid leaks caused by LPS partly mediated by the JNK signaling pathway. LXA4 and ATL ana logues could promote ERK phosphorylation Inhibitors,Modulators,Libraries in macro phages and monocytes. The reasons for these discrepancies are mainly due to differences in experi mental models, cell types and stimulators. Conclusions In summary, our results show that ATL inhibits release of NO and pro inflammatory cytokines in a concentra tion dependent manner. Moreover, ATL acts at the level of transcription in LPS stimulated microglia. A possible mechanism for this effect involves ATLs ability to acti vate a signaling cascade that results in repression of NF B, ERK and p38 MAPK activation in activated micro glia.

Given the fact that microglial activation Inhibitors,Modulators,Libraries contributes to the pathogenesis of neurodegenerative diseases, ATL may be considered as a potential therapeutic agent for neurodegenerative diseases involving neuroinflammation. Background Accumulating evidence points to neuroinflammation as an active participant in the progression DAPT secretase Notch of neurodegen erative diseases, such as Parkinsons disease and Alzheimers disease.