Previous studies in this laboratory have focused on the role of lymphocyte and monocyte products in modulating fibroblast growth and function. Unregulated production of these cytokines in certain chronic inflammatory lesions may be associated with pathologic disruption of normal tissue architecture as occurs in scleroderma and rheumatoid arthritis. In order to modulate these pathologic events it is necessary to define the mechanisms responsible. Therefore, our aim has been to study the molecular mechanisms of cytokine stimulation of fibroblast proliferation and collagen synthesis. The T cell derived fibroblast activating factor (FAF) has been characterized physicochemically and furthermore, messenger RNA for FAF obtained from activated T lymphocytes has been successfully translated in the xenopus oocyte translation system. The oocyte translation product is biologically and structurally indistinguishable from the FAF produced by the T cells. In additional studies, mononuclear cell-derived cytokine regulation of collagen synthesis has been studied. The protein synthetic data indicate that collagen production can be up- or down- regulated by different cytokines. FAF and IL1 appear to increase collagen production while GammaIFN inhibits synthesis. These studies are being extended to a molecular analysis of collagen synthesis using cDNA probes for pro Alpha(I), pro Alpha2(II) and (III) collagen chains in order to determine whether cytokine regulation is pre- or post-translational. If immunomodulators can be identified which significantly influence collagen synthesis, they may provide a target for modulating potentially pathologic sequlae in chronic inflammatory lesions.
