Abstract
Activation of human monocytes/macrophages (M phi) results in the production of metalloproteinases through a PGE2-cAMP-dependent pathway. Here we review our findings on the ability of IFN-gamma and IL-4 to modulate this signal transduction pathway as a result of the effect of these cytokines on eicosanoid synthesis. Preincubation for 1 hour with either IFN-gamma or IL-4 prior to stimulation with Con A caused a significant inhibition of M phi PGE2 production. Both of these cytokines also inhibited the Con A-induced production of interstitial collagenase and 92-kDa type IV collagenase/gelatinase. The inhibition of M phi metalloproteinase production by IFN-gamma and IL-4 was reversed by PGE2 or Bt2cAMP. Thus the suppression of eicosanoid synthesis by IFN-gamma and IL-4 is the primary mechanism by which these cytokines inhibit M phi metalloproteinase production. These findings demonstrate that IFN-gamma and IL-4 may have potent anti-inflammatory effects.
MeSH terms
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Arachidonic Acids / biosynthesis
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Bucladesine / pharmacology
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Collagenases / analysis
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Collagenases / metabolism
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Concanavalin A / pharmacology
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Dinoprostone / analysis
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Dinoprostone / metabolism
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Dinoprostone / pharmacology
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Extracellular Space / enzymology
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Humans
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Interferon-gamma / pharmacology*
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Interleukin-4 / pharmacology*
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Macrophages / drug effects
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Macrophages / enzymology*
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Macrophages / metabolism
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase Inhibitors
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Metalloendopeptidases / analysis
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / biosynthesis*
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Monocytes / drug effects
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Monocytes / enzymology*
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Monocytes / metabolism
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Phospholipases / analysis
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Phospholipases / metabolism
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Phospholipases A / pharmacology
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Recombinant Proteins
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Signal Transduction / drug effects
Substances
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Arachidonic Acids
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Matrix Metalloproteinase Inhibitors
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Recombinant Proteins
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Concanavalin A
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Interleukin-4
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Bucladesine
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Interferon-gamma
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Phospholipases
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Phospholipases A
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Collagenases
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Metalloendopeptidases
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Matrix Metalloproteinase 9
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Dinoprostone