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 monocyte chemotaxis to inflammatory stimuli. A newly identified chemotactic ligand is transforming growth factor beta (TGFBeta), a 25,000 Mr peptide originally defined by its ability to induce transformation of nonneoplastic cells in culture. More recently, TGFBeta has been shown to be a product of mononuclear cells and to induce the rapid formation of granulation tissue similar to that seen in tissue repair when injected subcutaneously. Our studies indicate that the mechanism of granulation tissue formation may be the consequence of TGFBeta stimulation of monocyte directed migration at concentrations of 0.1-1.0 pg/ml. In additional studies, monocytes were shown to possess specific cell surface receptors which bind 125-I-TGFBeta. At higher concentrations, TGFBeta stimulates monocytes to generate growth factors which may account for the fibroproliferative and fibrogenic response associated with TGFBeta injection. Additional studies defining activation and regulation of monocyte function have revealed that activation of macrophages induce IL2 receptor gene expression. This IL2 receptor expression may have an important immunoregulatory function. In ongoing studies, we have demonstrated that once recruited and activated, mononuclear cells generate fibroblast activating factors which stimulate fibroblast proliferation. In an experimental animal model the injection of bacterial cell walls induces hepatic granuloma formation which progresses to fibrotic lesions. The fibrosis is T cell dependent and does not occur in athymic animals or animals treated with the T cell inhibitor, cyclosporin A. These studies provide insight into the cellular and molecular mechanisms regulating immune-mediated alterations in connective tissue metabolism.