Mechanisms and modulation of macrophage activation

In the two decades following the discovery that macrophages can be activated by cytokines, there have been four major advances in our understanding of this phenomenon: (i) the identification of two biochemically defined, cytokine-inducible antimicrobial pathways, the enzymatic generation of superoxide and the enzymatic generation of nitric oxide; (ii) the identification of individual cytokines of known amino acid sequence capable of inducing these antimicrobial pathways and enhancing macrophage antimicrobial function; (iii) the demonstration of the utility of macrophage activating factors in the prevention and treatment of infectious diseases in man; and (iv) the discovery of the phenomenon of macrophage deactivation, together with the identification of several macrophage deactivating cytokines. This review briefly surveys each of these points, with emphasis on the regulation of production of the reactive oxygen intermediates and reactive nitrogen intermediates by two distinct but comparably suppressive cytokines, macrophage deactivation factor (MDF) and transforming growth factor-beta (TGF-beta).