|[Frontiers in Bioscience 2, d197-206, May 1, 1997]|
T CELL SIGNALING OF MACROPHAGE FUNCTION IN INFLAMMATORY DISEASE|
Robert D. Stout1 and Jill Suttles2
Program in Immunology, Departments of Microbiology1 and Biochemistry2, James H. Quillen College of Medicine at East Tennessee State University, Johnson City, TN, USA
Received 4/15/97; Accepted 4/18/97; On-line 5/1/97
The induction of these diverse macrophage functions is complex, differentially regulated, and poorly understood. Cytokines can stimulate or inhibit many of the macrophage functions described above but the modulating effect of many of the cytokines depends on the state of activation of the target macrophage population, the triggering signal, and timing (13,64,65). Although some exceptions have been noted, T cell cytokines such as IFN-gamma, IL-4, GM-CSF, and IL-3 generally can enhance accessory and co-stimulatory activity (13,29,66-69) and IFN-gamma, GM-CSF, and IL-3 can augment oxidative burst capacity (70-73). The combination of IL-2 plus IFN-gamma has been shown to induce TNF-alpha production and the combination of TNF-alpha and IFN-gamma have been shown to induce nitric oxide production (74-79). Thus, cytokines, especially the Th1 cytokines (IL2, TNF-alpha, IFN-gamma), can stimulate inflammatory and tissue destructive activities in macrophages.
In contrast, IL-10, TGF-beta, and, to a lesser degree, IL-4 (Th2 cytokines) inhibit the induction of oxidative burst and nitric oxide generation (54,57-59,80) and inhibit inflammatory cytokine production by macrophages (54-56,61,81), but do not affect (or enhance) IL-1Ra (IL-1 Receptor antagonist), IL-10 and TGF-beta production (61,82,83). Thus activated macrophages modulated by TGF-beta may display predominantly anti-inflammatory activities, such as secretion of IL-1Ra, IL-10, and TGF-beta.
Although these cytokines play an important role in modulating macrophage function, it is now clear that a critical mechanism by which T cells trigger these macrophage functions involves engagement of membrane-anchored receptor:ligand pairs during heterotypic adhesion between T cells and macrophages. Macrophage accessory, inflammatory, effector, and inhibitory functions have all been shown to be stimulated by paraformaldehyde fixed activated T cells or plasma membranes isolated from activated T cells (13,17-24,44,45,47). In each of these systems, pre-activation of the T cells is a requirement for cell contact-dependent signaling, suggesting the involvement of activation-induced membrane-anchored ligands on the T cells.