A metalloproteinase inhibitor blocks the shedding of soluble cytokine receptors and processing of transmembrane cytokine precursors in human monocytic cells.
A number of membrane-anchored cytokines and cytokine receptors are susceptible to yield soluble counterparts. Recently, peptide-hydroxamate metalloproteinase inhibitors have been reported to block the proteolytic processing of tumour necrosis factor (TNF)-alpha 55- and 75-kDa TNF receptors (TNF-R55 and TNF-R75), and interleukin (IL)-6R. In this report the authors studied the effect of an hydroxamate metalloproteinase inhibitor on the secretion of cytokines and the generation of cytokine soluble receptors by human myelomonoycytic cell lines and purified monocytes. 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 cytokines and cytokine receptors [TNF-alpha, macrophage colony-stimulating 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 sequences in the cleavage site of these proteins and differences found in the inhibitory concentration values suggest the existence of a metalloproteinase family displaying different substrate specificity. These results emphasize the important role of metalloproteinases as regulators of membrane expression and secretion of cytokines and cytokine receptors.
Gallea-Robache
S
S
Domaine Thérapeutique Immunologie, Romainville, France.
Morand
V
V
Millet
S
S
Bruneau
J M
JM
Bhatnagar
N
N
Chouaib
S
S
Roman-Roman
S
S
D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D018121:Receptors, Cytokine / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012995:Solubility; D019089:Stem Cell Factor / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D016207:Cytokines; D006877:Hydroxamic Acids; D007375:Interleukin-1; D015850:Interleukin-6; D011480:Protease Inhibitors; D011498:Protein Precursors; C106339:RU 36156; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019089:Stem Cell Factor; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D008666:Metalloendopeptidases