A METALLOPROTEINASE INHIBITOR BLOCKS THE SHEDDING OF SOLUBLE CYTOKINERECEPTORS AND PROCESSING OF TRANSMEMBRANE CYTOKINE PRECURSORS IN HUMAN MONOCYTIC CELLS

A number of membrane-anchored cytokines and cytokine receptors are sus ceptible to yield soluble counterparts, Recently, peptide-hydroxamate metalloproteinase inhibitors have been reported to block the proteolyt ic processing of tumour necrosis factor (TNF)-alpha 55- and 75-kDa TNF receptors (TNF-R55 and TNF-R75), and interleukin (IL)-6R, In this rep ort the authors studied the effect of an hydroxamate metalloproteinase inhibitor-on the secretion of cytokines and the generation of cytokin e soluble receptors by human myelomonocytic cell lines and purified mo nocytes, Whereas secretion of cytokines lacking a transmembrane domain precursor (IL-1 alpha, IL-1 beta, IL-6 or IL-10) is either unaffected or augmented, shedding/secretion of transmembrane domain-containing c ytokines and cytokine receptors [TNF-alpha, macrophage colony-stimulat ing factor (M-CSF), transforming growth factor (TGF)-alpha, stem cell factor (SCF), TNF-R55, TNF-R75, and IL-6R] was dramatically decreased in the presence of the metalloproteinase inhibitor, The diversity of s equences in the cleavage site of these proteins and differences found in the inhibitory concentration values suggest the existence of a meta lloproteinase family displaying different substrate specificity. These results emphasize the important role of metalloproteinases as regulat ors of membrane expression and secretion of cytokines and cytokine rec eptors. (C) 1997 Academic Press Limited.