Some cathepsins are excellent validation ubi quitously expressed and others are more cell specific. Cat S is thought to be restricted to antigen presenting cells and can be secreted by macrophages and microglia. Cat S is expressed in unstimulated microglia and is induced in microglia following spinal cord injury, where it contributes to neuropathic pain. There are several previous studies of microglia activation and Cat S but the results are inconsistent, and information relat ing it to IL4 treatment is very limited. IL4 increased the Cat S activity in tumor associated macrophages, and we found it selectively upregulated Cat S expression. Cat S was involved in microglial migra tion and invasion whereas, Cat K was only needed for substrate degradation and invasion, consistent with its essential role in bone resorption Inhibitors,Modulators,Libraries by osteoclasts.

After LPS treatment of primary rat microglia, we saw no change in Cat S expression. Several studies have used microglia cell lines, and this might account for the dis crepancies seen. Using the murine N Inhibitors,Modulators,Libraries 13 microglial cell line, one study reported that LPS decreased Cat S cellu lar levels and activity but increased its secretion, and Inhibitors,Modulators,Libraries another showed that basic fibroblast growth factor increased both intra and extracellular Cat S activity. In the BV 2 microglia cell line, LPS increased intra cellular levels of Cat S and Cat X but evoked secretion of Cat B, K, S and X. Interestingly, co stimulation of the P2X7 purinergic receptor was neces sary for secretion of enzymatically active Cat S from LPS treated rat primary microglia.

While there is limited information about the roles of Cat S in vivo based on its actions on T cell Inhibitors,Modulators,Libraries polarization, Cat S inhibi tors are being considered for use in autoimmune diseases. Conclusions Microglia migrate during normal CNS development and after disease or damage in the adult. Their functional roles will depend on their activation state, which itself Inhibitors,Modulators,Libraries is modulated by complex environmental cues. Classical and alternative activation states have been identified for microglia and are associated with generally damaging and reparative functions, respect ively. Regardless of their activation state, microglia must migrate and degrade the dense ECM to reach their tar get site. Thus, it is significant that classically and alterna tively activated microglial cells differed in their capacity for migration and invasion, and in levels and usage of several matrix degrading enzymes in vitro.

These diffe rences might determine how well they reach sellckchem target sites, and by providing specificity in matrix degradation, po tentially reduce bystander damage to the healthy ECM. Introduction Multiple sclerosis is a chronic inflammatory demye linating disease representing a major cause of neurological disability in the Western world.