Although OPG was not studied here, our previous work using tissue from a similar group of patients show Vandetanib 443913-73-3 that expression of this possible decoy TRAIL receptor was significantly reduced in active RA. However, OPG was only expressed by vas cular endothelial cells and some synovial macrophage popula tions, whereas the other TRAIL receptors studied here were widely expressed by infiltrating leucocytes. This report demonstrates a marked increase in TRAIL expres sion in synovial tissue from patients with several types of arthri tis that was largely due to the increased numbers of macrophages expressing TRAIL in the inflamed synovial tis sues. Due to the co expression of both death and decoy receptors in macrophages as seen in our finding, the net effect of this TRAIL upregulation on synovial tissue inflammatory cells is difficult to predict.

Several studies Inhibitors,Modulators,Libraries have shown that TRAIL induced apoptosis is regulated by the balance of the death and decoy receptors Inhibitors,Modulators,Libraries expressed by cells and the rela tive expression of TRAIL death or decoy receptors may be important in regulating apoptosis in active arthritides. How ever, while other upstream molecules stimulating apoptosis may be involved, the presence of cleaved caspase 3 in active RA synovial tissues observed in our study is consistent with the possibility of TRAIL binding to death receptor resulting in downstream signalling of apoptosis. The elevation of TRAIL expression Inhibitors,Modulators,Libraries is consistent with a recent report showing that soluble TRAIL levels are higher in RA syn ovial fluid compared with OA synovial fluid.

In contrast to the results reported here, Perlman and colleagues were unable to detect elevation of TRAIL or TRAIL receptors in syn ovial fibroblasts Inhibitors,Modulators,Libraries but did observe increased TRAIL R3 in RA synovial fluid macrophages. The different findings may have resulted from differences Inhibitors,Modulators,Libraries in the source of the samples, technique and also the different antibodies used in each study. A study by Ichikawa and colleagues was per formed both on synovial fibroblasts in culture and on the syn ovial membrane but was limited to the investigation of only TRAIL R1 and TRAIL R2. Their study reported that only TRAIL selleck compound R2 was expressed in the synovial tissues in situ but not TRAIL R1. We noted high expression of TRAIL R1 and R2 in the cyto plasm and perinuclear regions of the cell, respectively. In con trast the cell surface membrane only weakly stained for the presence of these receptors. This is consistent with studies of apoptosis in melanoma cells that have reported nuclear local isation of TRAIL R2 and may be one possible mechanism of escape from apoptosis.