Modulation of TIMP-1 synthesis by antiinflammatory cytokines and prostaglandin E2 in interleukin 17 stimulated human monocytes/macrophages.
OBJECTIVE
To examine the regulation of tissue inhibitor of metalloproteinase 1 (TIMP-1) synthesis by interleukin 17 (IL-17) stimulated human monocytes/macrophages in primary culture in the presence of prostaglandin E2 (PGE2) and antiinflammatory cytokines, and to compare this with the regulation of matrix metalloproteinase (MMP-9) production.


METHODS
IL-17 stimulated human monocytes isolated from the peripheral blood of healthy donors were cultured in the presence of PGE2, cyclic adenosine monophosphate (cAMP) mimetics (IBMX, cAMP, forskolin, cholera toxin), or antiinflammatory cytokines (IL-4, IL-10, IL-13), or with protein kinase inhibitors of diverse specificity. MMP-9 and TIMP-1 were measured using specific ELISA, while expression of specific messenger RNA was determined by Northern blotting.


RESULTS
IL-17 stimulated an increased level of MMP-9 production relative to TIMP-1 production in monocytes/macrophages. Stimulation was accompanied by upregulation of specific MMP-9 mRNA expression relative to TIMP-1 mRNA. Exogenous PGE2, cAMP, and cAMP-mimetics completely inhibited both basal and IL-17 induced MMP-9 synthesis, while only IL-17 induced TIMP-1 synthesis was abrogated. The same effect was found for the antiinflammatory cytokines. Both basal and IL-17 induced production of TIMP-1 involved p42/44 and p38 kinases and nuclear factor kappaB signaling pathways.


CONCLUSIONS
The excess of MMP-9 over TIMP-1 production, and decreased inhibition of MMP-9 activity in chronic rheumatoid diseases, may result in cartilage degradation and joint destruction.
Jovanovic
D V
DV
Osteoarthritis Research Unit, H pital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Québec, Canada.
Di Battista
J A
JA
Martel-Pelletier
J
J
Reboul
P
P
He
Y
Y
Jolicoeur
F C
FC
Pelletier
J P
JP
D000328:Adult; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D020381:Interleukin-17; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D000242:Cyclic AMP; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone