IL-18 initiates release of matrix metalloproteinase-9 from peripheral blood mononuclear cells without affecting tissue inhibitor of matrix metalloproteinases-1: Suppression by TNFα blockage and modulation by IL-10

Marcel Nold, Andreas Goede, Wolfgang Eberhardt, Josef Pfeilschifter, Heiko Mühl

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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-α (TNFα 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 TNFα. MMP-9 production was dependent on endogenous production of TNFα, as detected by use of neutralizing monoclonal antibodies. Whereas IL-18 and TNFα induced the protease, MMP-9 release was not mediated by IFNγ. 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 TNFα production in these responses, and relates IL-18 biological functions to the pathological role of MMP-9.

Original languageEnglish
Pages (from-to)68-75
Number of pages8
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number1
Publication statusPublished - 1 Jan 2003
Externally publishedYes


  • Inflammation
  • Interleukin-18
  • Matrix metalloproteinase-9
  • Peripheral blood mononuclear cells

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