Soluble CD137 (4-1BB) ligand is released following leukocyte activation and is found in sera of patients with hematological malignancies

Expression of CD137 ligand (4-1BBL), a member of the TNF family of proteins , has been reported on several types of APCs, various carcinoma cells, and can be induced on activated T cells. In this study, we report that the solu ble ligand was released constitutively at low levels from leukocytes and at higher levels following cellular activation. Release from cells was blocke d by addition of a metalloproteinase inhibitor which concomitantly caused t he accumulation of 4-1BBL on the cell surface. In addition, we show that a soluble form of 4-1BBL was present at high levels in the sera of some patie nts with various hematological diseases, but only at low levels in healthy donors. Soluble 4-1BBL was active in that it competed with recombinant 4-1B BL for binding to the 4-1BB receptor and was able to costimulate IL-2 and I FN-gamma release from peripheral T cells. These results indicate that the r elease of soluble 4-1BBL from the cell surface is mediated by one or more s heddases and likely regulates 4-1BB-4-1BBL interactions between cells in vi vo. Cleavage of 4-1BBL to an active soluble form would alter both proximal and distal cellular responses, including cell survival and costimulatory or inflammatory responses, that are mediated through the 4-1BB pathway. This, in turn, would likely alter disease progression or outcome.