Stimulation of 92-kd gelatinase (matrix metalloproteinase 9) production by interleukin-17 in human monocyte/macrophages: a possible role in rheumatoid arthritis.
OBJECTIVE
To examine the cellular mechanisms by which the proinflammatory cytokine interleukin-17 (IL-17) induces the synthesis of 92-kd gelatinase (matrix metalloproteinase 9 [MMP-9]) by human monocyte/ macrophages in primary culture.


METHODS
IL-17-stimulated human monocytes isolated from the peripheral blood of healthy donors were cultured in the presence of antiinflammatory cytokines, neutralizing antibodies against IL-1beta, tumor necrosis factor alpha (TNFalpha), or IL-1 receptor antagonist, and with protein kinase inhibitors of diverse specificity. MMP measurements were performed using specific enzyme-linked immunosorbent assays, while the expression of specific messenger RNA was determined by Northern blotting. Detection of phosphorylated proteins and specific transcriptional factors was performed by Western blotting and by gel retardation experiments, respectively.


RESULTS
Biologically active IL-17 was detected in the synovial fluid of patients with rheumatoid arthritis. IL-17-induced MMP-9 production in human monocyte/ macrophages was dependent on endogenous prostaglandin E2 synthesis and related to autocrine stimulation by TNFalpha, but was IL-1beta independent. This activation involves both p42/44 and p38 kinases and nuclear factor kappaB. IL-17-inducible activator protein 1 and signal transducer and activator of transcription 1/3 may transactivate the MMP-9 promoter.


CONCLUSIONS
IL-17 may contribute to an unbalanced production of proinflammatory cytokines and MMP-9 in diseased articular joint tissues by interacting with the macrophages in the rheumatoid synovium.
Jovanovic
D V
DV
Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Quebec, Canada.
Martel-Pelletier
J
J
Di Battista
J A
JA
Mineau
F
F
Jolicoeur
F C
FC
Benderdour
M
M
Pelletier
J P
JP
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000503:physiopathology; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D020381:Interleukin-17 / Q000032:analysis / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D008565:Membrane Proteins; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013582:Synovial Fluid / Q000737:chemistry; D015534:Trans-Activators / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D020381:Interleukin-17; D007527:Isoenzymes; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone