CHRONIC INFLAMMATION AND IMMUNOMODULATION OF CONNECTIVE TISSUE METABOLISM

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Mononuclear cells generate a variety of hormone-like proteins termed growth factors which are instrumental in the evolution and resolution of inflammatory reactions. Many of these growth- regulatory molecules have multi-functional properties. For example, transforming growth factor beta (TGF-beta) is a potent chemoattractant and functions as an inducing agent for other monocyte-derived growth hormones. Once secreted, these growth- promoting molecules provide a network of signals which regulate other inflammatory cells as well as fibroblast proliferation and angiogenesis. Although TGF-beta induces IL1 production, it is also a potent inhibitor of IL1-dependent lymphocyte proliferation. Inhibition of cell division occurs late in the activation sequence of the lymphocytes since neither gene expression of IL2 or IL2 receptors is suppressed. Our recent studies have documented enhanced levels of TGF-beta within a chronic inflammatory lesion characterized by profound immunosuppression. This immunosuppressive activity was blocked with an antibody to TGF- beta. The primary source of this TGF-beta within the lesion appears to be the macrophages. Macrophages constitutively express TGF-beta mRNA but only synthesize and secrete the polypeptide when stimulated. These observations suggest that TGF-beta might provide a negative feedback mechanism to reverse the inflammatory response, yet enable IL1, TNF and other monokines to continue modulation of tissue repair. Thus, the biological effects of TGF-beta may serve to protect the host from prolonged inflammatory events and to promote the healing of inflamed tissues. In addition to the secretion of growth hormones, monocytes activated at an inflammatory site lose their ability to chemotax to certain inflammatory stimuli. One mechanism for this cessation of migration appears to be the modulation of chemotactic ligand receptors. Activation by bacterial products, certain viruses and/or lymphocyte products (gamma IFN) causes a down-regulation of C5a receptors and a corresponding loss of ability to chemotax to C5a. Consequently, monocytes once activated, likely become unable to migrate further to inflammatory stimuli and therefore accumulate at the inflammatory site.