Inter estingly, CCL2, known to be involved in neuroinflamma tory processes, not only promotes leukocyte references chemotaxis but also compromises the BBB. In fact, CCL2 mediates redistribution of tight junction proteins and reorganization of the actin cytoskeleton in brain endothe lial cells, leading to altered BBB functions. We thus suggest that induced secretion of CCL2 by HCMECs Inhibitors,Modulators,Libraries may be one of the processes elicited by TWEAK to in crease BBB permeability. Our results suggest that TWEAK induced the expres sion of MMP 9 through the activation of MAPK signal ing pathway in human cerebral endothelial cells. The ability of TWEAK to modulate MMP 9 expression was previously reported in a few studies including the work of Chicheportiche et al. in 2002. Li et al.

have also shown that TWEAK affects the expression of sev eral genes of the MMP family in skeletal muscle. It was also proposed that TWEAK plays a role in MMP 3 and MMP 1 up regulation. Finally, TWEAK has been shown to enhance MMP Inhibitors,Modulators,Libraries 9 expression in several cell types, including macrophages, C2C12 myotubes, and mouse astrocytes. Nevertheless, the ex pression of these MMPs and their potential role in struc tural and functional deterioration of BBB during pathological conditions remain largely unknown. Inhibitors,Modulators,Libraries Asahi et al. demonstrated that MMP 9 has a direct ef fect on the permeability of the neurovascular unit. Inter estingly, we show that cerebral endothelial cells under TWEAK treatment express more of the pro MMP 9 than of the active MMP 9. This is in agreement with several studies involving gelatin zymography showing that it is essentially pro MMP 9 that is induced in glial cells, neurons, and endothelial Inhibitors,Modulators,Libraries cells.

This observation may reflect a rapid and local activation of MMP 9 in these cells by sharp activation mechanisms. Our study provides the first evidence showing that in endothelial cells, it is only the Inhibitors,Modulators,Libraries cellular MMP 9, presumably including membrane bound MMP 9, that is increased by TWEAK, EPZ5676 while there is no induction of secreted MMP 9. We hypothesize that MMP 9 may play a local role in cytosolic and membrane proteolytic activ ity under physiological and pathological conditions. A number of in vitro results, including some from our laboratory, indicate that pro and active forms of MMP 9 are also localized in the membrane, for example in neural cells. Previous studies suggest that activa tion of MMP 9 pro enzyme occurs by binding at the cell surface, and that the activated enzyme is then rapidly degraded, preventing excess activity. Therefore, only very low levels of active MMP 9 may be present in cells at any given time.