CHRONIC INFLAMMATION AND IMMUNOMODULATION OF CONNECTIVE TISSUE METABOLISM

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Mononuclear cell recruitment and activation are central to the initiation, perpetuation and resolution of chronic inflammatory lesions. Investigations in this laboratory continue to characterize mechanisms of leukocyte chemotaxis to inflammatory stimuli. Transforming growth factor beta (TGF-beta) produced by platelets, lymphocytes and monocytes is an extremely potent chemoattractant from monocytes and neutrophils at femtomolar concentrations. This level of activity may make TGF-beta the most potent known chemotactic substance for leukocytes. At higher concentrations, TGF beta activates monocytes to elaborate polypeptide growth factors. TGF-beta induces increased transcription and translation of interleukin 1 beta and tumor necrosis factor consistent with the ability of TGF-beta to induce fibrosis and angiogenesis in vivo. While TGF-beta may promote wound healing by such a mechanism, TGF-beta also functions as an extremely active immunosuppressive agent. At femtomolar concentrations, TGF-beta inhibits IL1-dependent T lymphocyte proliferation. The inhibitory effect of TGF-beta occurs distal to the growth factor-receptor interaction and does not inhibit signal transduction leading to IL2 or IL2 receptor transcription or expression. Thus, TGF-beta selectively down-regulates lymphocyte mitogenesis, but does not appear to inhibit lymphokine production. This immunosuppressive mechanism of action distinguishes TGF-beta from cyclosporin A (CsA), a fungal metabolite which specifically inhibits T lymphocyte proliferation and lymphokine synthesis. In a recently completed randomized double-blind clinical trial, the immunosuppressive activity of CsA has been found to be of therapeutic benefit in the treatment of rheumatoid arthritis. The efficacy of TGF-beta in reversing erosive polyarthritis is under study in experimental animal models.