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Suppression of metalloproteinase biosynthesis in human alveolar macrophages by interleukin-4
S Lacraz1, L Nicod, B Galve-de Rochemonteix
1Immunology and Allergy Division, Hôpital Cantonal Universitaire, Geneva, Switzerland.
Abstract:
To study the interaction of lymphocytes and macrophages in the control of extracellular matrix turnover, we determined the effects of several soluble T cell products on mononuclear phagocyte production of metalloproteinases. Cytokines including IL-2, IL-4, IL-6, tumor necrosis factor alpha (TNF alpha), GM-CSF, and IFN-gamma were each tested for capacity to modulate macrophage metalloproteinase and tissue inhibitor of metalloproteinases (TIMP) expression. The addition of IL-4 to cells cultured under basal conditions caused a dose-dependent suppression in the release of 92-kD type IV collagenase without affecting TIMP production. 92-kD enzyme secretion was inhibited by 50% with 1-2 ng/ml of IL-4 and by 90% with 10 ng/ml of IL-4. When cells were first exposed to killed Staphylococcus aureus to induce metalloproteinase production, IL-4 potently blocked the stimulated release of both interstitial collagenase and 92-kD type IV collagenase, again without effect upon TIMP. Metabolic labeling experiments and Northern hybridizations demonstrated that IL-4 exerted its action at a pretranslational level. Furthermore, IL-4 possessed the capacity to inhibit metalloproteinase expression even in the relatively immature peripheral blood monocyte. As reported previously (Shapiro, S. D., E. J. Campbell, D. K. Kobayashi, and H. G. Welgus. 1990. J. Clin. Invest. 86:1204), IFN-gamma suppressed constitutive macrophage production of 92-kD type IV collagenase. Despite the frequent antagonism observed between IL-4 and IFN-gamma in other systems, the combination of these two agents lowered metalloproteinase biosynthesis dramatically, whereas IL-4 opposed the IFN-gamma-stimulated production of cytokines (IL-1 and TNF alpha). IL-6 had only minimal effect upon metalloproteinase production, but appeared to specifically augment TIMP release. In summary, cytokines released by activated T cells may profoundly reduce the capacity of the macrophage to mediate extracellular matrix degradation.
Insights
T cell cytokines, particularly interleukin-4 (IL-4), significantly suppress macrophage metalloproteinase production, impacting extracellular matrix turnover. This cytokine-mediated regulation offers insights into immune cell interactions controlling tissue remodeling.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Lymphocytes and macrophages interact to regulate extracellular matrix (ECM) turnover.
- Metalloproteinases (MMPs) and their inhibitors (TIMPs) are key regulators of ECM degradation.
- T cell-derived cytokines influence macrophage function.
Purpose of the Study:
- To investigate the effects of soluble T cell products on macrophage MMP and TIMP production.
- To elucidate the role of specific cytokines, including IL-4 and IFN-gamma, in modulating ECM-degrading enzymes.
Main Methods:
- Cultured mononuclear phagocytes (macrophages) were treated with various cytokines (IL-2, IL-4, IL-6, TNF-alpha, GM-CSF, IFN-gamma).
- MMP and TIMP production was assessed under basal and stimulated (Staphylococcus aureus) conditions.
- Pretranslational regulation was investigated using metabolic labeling and Northern hybridization.
Main Results:
- Interleukin-4 (IL-4) dose-dependently suppressed the release of 92-kD type IV collagenase without affecting TIMP production.
- IL-4 inhibited both constitutive and Staphylococcus aureus-induced MMP release at a pretranslational level, even in monocytes.
- IFN-gamma also suppressed 92-kD type IV collagenase, and its combination with IL-4 dramatically reduced MMP biosynthesis.
Conclusions:
- Activated T cell cytokines, especially IL-4, can profoundly inhibit macrophage-mediated ECM degradation.
- IL-4 acts at the pretranslational level to reduce MMP expression.
- Cytokine interplay (e.g., IL-4 and IFN-gamma) fine-tunes macrophage matrix-remodeling capabilities.
