Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor α required as a costimulatory factor for interferon γ-induced activation

Abstract

Interleukin 10 (IL-10) inhibits Interferon γ-induced macrophage activation for cytotoxicity against larvae of the human parasite Schistosoma mansoni by suppressing production of the toxic effector molecule nitric oxide (NO). In this study, the mechanism of IL-10 action was identified as inhibition of endogenous tumor necrosis factor α (TNF-α) production by interferon γ-activated macrophages. TNF-α appears to serve as a cofactor for Interferon γ-mediated activation, since both schistosomulum killing and NO production were inhibited by anti-TNF-α antibody, whereas TNF-α alone was unable to stimulate these macrophage functions. IL-10 blocked TNF-α production by interferon γ-treated macrophages at the levels of both protein and mRNA synthesis. Addition of exogenous TNF-α reversed IL-10-mediated suppression of macrophage cytotoxic activity as well as NO production. Likewise, addition of a macrophage-triggering agent (bacterial lipopolysaccharide or muramyl dipeptide), which induced the production of TNF-α, also reversed the suppressive effect of IL-10 on cytotoxic function. In contrast to IL-10, two other cytokines, IL-4 and transforming growth factor β, which also inhibit macrophage activation for schistosomulum killing and NO production, did not substantially suppress endogenous TNF-α production. These results, therefore, describe a separate pathway by which macrophage microbicidal function is inhibited by the down-regulatory cytokine IL-10.