In our efforts to dissect selleck chemicals llc the upstream signaling events that are involved in MCP 1 release from astrocytes, using both the pharmaco logical as well as genetic approaches we demonstrated the role of MAPK and PI3KAkt in PDGF BB mediated induction of MCP 1 from Inhibitors,Modulators,Libraries astrocytes. The involvement of MAPK and PI3KAkt Inhibitors,Modulators,Libraries pathways in the induction of MCP 1 expression are in agreement with the role these pathways play in induction of this chemokine in other cell types including osteoblasts, mesangial cells and endothelial cells. The transcription factor, NF��B is known Inhibitors,Modulators,Libraries to play a key role in PDGF BB signaling and also in the expression of proinflammatory cytokines chemokines including MCP 1. Consistent with other reports, our studies also revealed that PDGF BB mediated induction of MCP 1 involved both NF��B acti vation and its binding to the MCP 1 promoter.

It was next of interest to explore the functional rele vance of PDGF BB mediated induction of MCP 1. Based on the proximity of astrocytes to the endothelial barrier, we rationalized that induced expression Inhibitors,Modulators,Libraries of MCP 1 in PDGF BB treated astrocytes could play a role in barrier disrupt the endothelial barrier while enhancing neuroin flammation, which can have serious ramifications in HAND. In summary, our studies have mapped out a detailed molecular pathway of PDGF BB mediated MCP 1 ex pression in astrocytes involving ERK12, JNK MAPK ac tivation, with the subsequent activation of NF��B resulting in increased MCP 1 expression, ultimately leading to increased monocyte transmigration and increased permeability in the brains of individuals infected with HIV.

integrity. Intriguingly, conditioned media from PDGF BB treated astrocytes did indeed increase monocyte transmigration and this effect was attributable to MCP 1 as Inhibitors,Modulators,Libraries demonstrated in the blocking antibody experiments. This role of MCP 1 is in agreement with the findings reported by Eugenin et al. who have demonstrated that HIV infected leukocyte transmigration across a tissue culture model of human BBB involved MCP 1. In addition to disrupting the barrier permeability, MCP 1 also manifested increased monocyte recruitment. This latter function is in keeping with its known roles both as a chemoattractant and as a biomarker of HIV neuro pathogenesis. The function of MCP 1 demonstrated in this study can have ramifications in the pathogenesis of HAND.

Based on the proximity of astrocytes to the endothelium and their ability to secrete both PDGF BB and the che mokine MCP 1 as well as their abundance this in the CNS, it can be argued that during HIV 1 infection, viral proteins can initiate a toxic cascade that can be self perpetuating. HIV 1HIV 1 Tat can trigger increased expression of PDGF BB, which in turn, can lead to increased MCP 1 expression that can manifest as an amplified influx of monocytes into the CNS.