[Frontiers in Bioscience 2, d197-206, May 1, 1997]
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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

3. MULTIPLE ROLES OF MACROPHAGES IN INFLAMMATORY DISEASES.

The cellular infiltrates of active sclerotic lesions are dominated by cells of the monocytic lineage (macrophages and microglial cells) (6-8). These macrophages can display very diverse functions in sclerotic lesions (Fig. 1). They can function as accessory cells, presenting antigen and providing co-stimulatory ligands (e.g., CD80, CD86, and CD48) and co-stimulatory cytokines (e.g., IL-1 and IL-12) to the infiltrating T cells (10,13,32-36). Macrophages can be activated to produce prodigious amounts of pro-inflammatory cytokines such as TNF-alpha, IL-1, and IL-6, chemoattractant cytokines such as IL-8 and macrophage inflammatory protein (MIP)-1 alpha/beta (13,37), and pro-inflammatory products of arachidonic acid metabolism (13,38).

Figure 1. The diverse functions of macrophages. Macrophages are capable of many functional activities and contribute both to the initiation of cell-mediated immune response and to the effector limb of those responses. During the course of the response, macrophages can display, at different times, both inflammatory and anti-inflammatory activities.

TNF-alpha, in particular, appears to play a critical role in the pathogenesis of experimental allergic encephalomyelitis, the murine model of multiple sclerosis, insofar as administration of anti-TNF-alpha antibodies in vivo inhibits the development of experimental allergic encephalomyelitis (39).

Interestingly, in addition to the inflammatory and destructive activities listed above, macrophages have the potential to contribute to the remission of the inflammatory episode, although the degree to which they participate in remission has not yet been directly assessed. Macrophages can be induced to generate toxic reactive oxygen and nitrogen intermediates(13,40-45) and to secrete "tissue restructuring" metalloproteinases (13,46-48), each of which have been hypothesized to directly contribute to the demyelinization process (49-51). Macrophages also can be induced to secrete cytokines which inhibit macrophage accessory, inflammatory, and effector functions. IL-10, which is produced by both macrophages and T cells, down-regulates expression of costimulatory molecules such as CD86 (52,53), inhibits the production of IL-1 and TNF-alpha and reduces generation of reactive oxygen and nitrogen intermediates (54-57). Transforming growth factor-beta (TGF-beta), which is produced by many cell types including macrophages and T cells, also inhibits generation of reactive oxygen and nitrogen intermediates (58,59), especially in synergy with IL-10 (43,57,60), and is hypothesized to play a critical role in resolution of inflammatory lesions in experimental allergic encephalomyelitis (61-63).