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Regulation of monocyte/macrophage metalloproteinase production by cytokines
1Cellular Immunology Section, National Institute of Dental Research, National Institutes of Health, Bethesda, MD.
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.
Insights
Interferon-gamma (IFN-gamma) and Interleukin-4 (IL-4) suppress monocyte/macrophage metalloproteinase production by inhibiting prostaglandin E2 (PGE2) synthesis. This indicates potent anti-inflammatory effects for these cytokines.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Human monocytes/macrophages (M phi) produce metalloproteinases via a PGE2-cAMP-dependent pathway.
- Metalloproteinases play roles in inflammatory processes.
Purpose of the Study:
- To investigate the modulatory effects of IFN-gamma and IL-4 on M phi metalloproteinase production.
- To elucidate the role of eicosanoid synthesis in this modulation.
Main Methods:
- Preincubation of M phi with IFN-gamma or IL-4 before Con A stimulation.
- Measurement of PGE2, interstitial collagenase, and 92-kDa type IV collagenase/gelatinase production.
- Assessment of the effects of PGE2 or Bt2cAMP on cytokine-induced inhibition.
Main Results:
- IFN-gamma and IL-4 significantly inhibited Con A-induced PGE2 production in M phi.
- These cytokines also suppressed the production of interstitial collagenase and 92-kDa type IV collagenase/gelatinase.
- The inhibitory effects of IFN-gamma and IL-4 on metalloproteinase production were reversed by exogenous PGE2 or Bt2cAMP.
Conclusions:
- Suppression of eicosanoid synthesis is the primary mechanism by which IFN-gamma and IL-4 inhibit M phi metalloproteinase production.
- IFN-gamma and IL-4 demonstrate potent anti-inflammatory effects by modulating this pathway.