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Department of Immunology, Inflammation, and Pulmonary Diseases, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08540; and
Med. Klinik III, Klinikum Grosshadern, Ludwig-Maximiliam University, Muenchen, Germany
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 soluble ligand was released constitutively at low
levels from leukocytes and at higher levels following cellular
activation. Release from cells was blocked by addition of a
metalloproteinase inhibitor which concomitantly caused the 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 patients with
various hematological diseases, but only at low levels in healthy
donors. Soluble 4-1BBL was active in that it competed with recombinant
4-1BBL for binding to the 4-1BB receptor and was able to costimulate
IL-2 and IFN-
release from peripheral T cells. These results
indicate that the release of soluble 4-1BBL from the cell surface is
mediated by one or more sheddases and likely regulates 4-1BB-4-1BBL
interactions between cells in vivo. 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.
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