IL-18 initiates release of matrix metalloproteinase-9 from peripheral blood mononuclear cells without affecting tissue inhibitor of matrix metalloproteinases-1: suppression by TNF alpha blockage and modulation by IL-10.
The proinflammatory cytokine interleukin (IL)-18 appears to be involved in the etiology of a variety of pathological conditions, among them rheumatoid arthritis and atherosclerosis as well as tumor growth and metastasis. As biological activity of matrix metalloproteinase-9 (MMP-9) has been identified as a hallmark in the pathogenesis of these diseases, effects of IL-18 on MMP-9 production by human peripheral blood mononuclear cells (PBMC) were investigated. Moreover, effects of immunopharmacological intervention by anti-tumor necrosis factor-alpha (TNFalpha) or IL-10 were evaluated. Here we report that IL-18 augmented production of MMP-9 by PBMC. The potency of IL-18 to induce release of MMP-9 from PBMC was comparable with that of TNFalpha. MMP-9 production was dependent on endogenous production of TNFalpha, as detected by use of neutralizing monoclonal antibodies. Whereas IL-18 and TNFalpha induced the protease, MMP-9 release was not mediated by IFNgamma. IL-18 also induced secretion of MMP-9 from human whole blood cultures. Antiinflammatory IL-10 efficiently downregulated release of MMP-9 from unstimulated and IL-18-activated PBMC. In contrast to MMP-9, secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) was not augmented by IL-18. Addition of IL-10 enhanced release of TIMP-1 from PBMC. The present study broadens the current pattern of IL-18 proinflammatory actions on PBMC, emphasizes the pivotal role of intermediate TNFalpha production in these responses, and relates IL-18 biological functions to the pathological role of MMP-9.
Nold
Marcel
M
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Goede
Andreas
A
Eberhardt
Wolfgang
W
Pfeilschifter
Josef
J
Mühl
Heiko
H
D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*
D018836:Inflammation Mediators; D020382:Interleukin-18; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D020780:Matrix Metalloproteinase 9