Regulation of monocyte/macrophage metalloproteinase production by cytokines.
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.
Cellular Immunology Section, National Institute of Dental Research, National Institutes of Health, Bethesda, MD.
L M
LM
Wahl
M L
ML
Corcoran
D001095:Arachidonic Acids / Q000096:biosynthesis; D003994:Bucladesine / Q000494:pharmacology; D017364:Collagenases / Q000032:analysis / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010740:Phospholipases / Q000032:analysis / Q000378:metabolism; D010741:Phospholipases A / Q000494:pharmacology; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects
D001095:Arachidonic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D003208:Concanavalin A; D015847:Interleukin-4; D003994:Bucladesine; D007371:Interferon-gamma; D010740:Phospholipases; D010741:Phospholipases A; D017364:Collagenases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone