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.