title: Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10.
abstract: The findings reviewed above leave no doubt as to the complexity of actions of TGF-beta, IL-4, and IL-10 on monocytes/macrophages. Along with MDF, whose actions were recently reviewed elsewhere, TGF-beta, IL-4, and IL-10 are the only presently known, purified cytokines that have been shown to have strong macrophage-deactivating effects. However, none of them can be categorized as purely macrophage deactivating since they also exert macrophage-activating effects. In vitro, their effects, both in terms of extent and direction (activating vs. deactivating), are strongly influenced by the stimulation conditions (e.g., triggering signal, cytokine concentration, timing of cytokine addition), the species (mouse vs. human), the source (blood vs. peritoneal, alveolar, colostral) and the state of differentiation/activation of the macrophage (e.g., resting vs. inflammatory). In addition, TGF-beta, as well as IL-4 and IL-10, up- and/or downregulates the function of several cell types other than macrophages, which further hampers our ability to predict, on the basis of in vitro experiments with macrophages, possible effects during an immune response in vivo. Despite this complexity, the highly reductive approach of in vitro studies has revealed important differences in the ability of TGF-beta, IL-4, and IL-10 to modulate the phenotype of monocytes/macrophages. The disparities have been most striking with regard to the secretory function of monocytes/macrophages (see Table 2). First, TGF-beta, IL-4, and IL-10 have a different spectrum of activity. Thus, TGF-beta, but not IL-4 or IL-10, can induce resting human monocytes to produce TNF, IL-1, and IL-6. Second, they affect monokine and RNI and ROI production to a different extent. For example, IL-10 is an approximately 25-fold more potent suppressor of LPS-induced TNF production by mouse macrophages than is TGF-beta. Third, they differ in their ability to overcome additional activating stimuli, so that in the presence of LPS, IL-4, but not TGF-beta or IL-10 suppresses IFN gamma-induced RNI release. Fourth, their macrophage-deactivating effects require different stimulation conditions. Thus, IL-4, but not TGF-beta, interferes with RNI release strongly only after preincubation of the macrophages. Finally, these agents deactivate macrophages by distinct mechanisms. For example, IL-10 causes massive downregulation of TNF mRNA, whereas TGF-beta suppresses TNF release on a translational level. It will be a challenge to define clinical applications for these potent macrophage modulators on the basis of their different spectrum of activities. For TGF-beta and IL-4 such studies have already been initiated.
authors.affiliation: Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
authors.forename: C
authors.initials: C
authors.lastname: Bogdan
authors.forename: C
authors.initials: C
authors.lastname: Nathan
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000032:analysis; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009584:Nitrogen / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D006649:Histocompatibility Antigens; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D009584:Nitrogen