Studies on the mechanisms of monocyte/macrophage activation and resultant production of biochemial mediators continue with the goal of relating these events to the regulation of connective tissue metabolism and immune dysfunction in various disease states. Previous findings utilizing guinea pig peritoneal macrophages revealed that collagenase production was inhibited by indomethacin, dexamethasone or colchicine. In contrast to collagenase production our recent studies demonstratee that another macrophage product, fibroblast activating factor (FAF), which enhances collagen synthesis was relatively unaffected by these same anti-inflammatory agents. These results suggest differential regulation of the pathway for destruction and formation of connective tissue. We have also extended these studies in the human system. Con A stimulates human monocytes to release significant amounts of collagenase through a prostaglandin dependent pathway. Whereas dexamethasone inhibits monocyte collagenase at the PGE-2 level, colchicine inhibited collagenase synthesis without effect on PGE-2 synthesis. In contrast, the inhibition of collagenase by retinoic acid was accompanied by a significant increase in PGE-2 synthesis. Since neither the inhibition by colchicine or retinoic acid could be reversed by PGE-2, these studies provide insight into the intracellular events leading to monocyte collagenase synthesis and secretion and also provide information on the mechanism of action of certain inflammatory drugs. Interferon-"""""""" (IFN-"""""""") which is a potent immunomodulator of many macrophage functions has been shown to bind to purified human monocytes as well as monocyte like cell lines (U937 and HL60). Radioiodinated recombinant IFN-"""""""" bound to human monocytes and the cell lines in a specific and saturable manner. Saturation of binding sites occurred at 10 minus 9M and there were 4,000 specific binding sites per cell for both monocytes and cell lines. Purified lymphocyte derived IFN-"""""""" as well as recombinant rIFN-"""""""" competed for binding sites with 125I-rIFN"""""""". Additionally, there was no inhibition of binding of the 125I-rIFN-"""""""" by rIFN-3 or rIFN-2.
