Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis.
Gelatinases (type IV collagenases) produced by normal peripheral blood leukocytes were studied by the use of a substrate conversion assay. When monocytes were stimulated with IL-1 beta discrete amounts of a 85-kDa gelatinase were detected. This type of gelatinase comigrated with a phorbol ester-inducible metalloproteinase from human tumor cells. The levels of induction of the monocytic enzyme after stimulation with IL-1, double-stranded RNA, LPS, and mitogens paralleled those of the secondary cytokine IL-6. When peripheral blood neutrophils were stimulated with IL-8 or PMA significant amounts of a 91-kDa neutrophil gelatinase were released, whereas with IL-1 beta no effect was observed. Both neutrophil and monocyte gelatinases cross-reacted in immunoprecipitation experiments with tumor cell-derived gelatinases. Further evidence for structural similarity between the IL-1-inducible monocytic (85 kDa) and the IL-8-regulated neutrophilic (91 kDa) gelatinases was obtained after purification of the proteins to homogeneity: both gelatinases possessed an identical amino terminal amino acid sequence and appeared as truncated forms of gelatinase from tumor cells. Synovial fluids of arthritic joints contained extremely high concentrations of the 91-kDa gelatinase. The concentrations of this type of gelatinase were correlated with the titers of the marker cytokine IL-6. The controlled production and activity of leukocyte-derived gelatinase may play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. In the arthritis patient this enzyme might contribute to the pathogenesis of joint destruction and might constitute a useful marker of disease status.
Rega Institute for Medical Research, University of Leuven, Belgium.
G
G
Opdenakker
S
S
Masure
B
B
Grillet
J
J
Van Damme
D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000201:enzymology; D016207:Cytokines / Q000494:pharmacology*; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000494:pharmacology; D007962:Leukocytes / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology; D009504:Neutrophils / Q000201:enzymology; D013582:Synovial Fluid / Q000201:enzymology
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008666:Metalloendopeptidases