The objectives of this project are to unravel the mystery of scleroderma in order to make possible more effective therapy and/or preventive measures. In previous studies we have described a 6-9,000 molecular weight inhibitor of interleukin-1 (IL-1), produced by human peripheral blood monocytes in culture, which has the interesting characteristic of acting as a stimulator of fibroblasts. Cultured peripheral blood monocytes from patients with scleroderma produce increased amounts of this IL-1 inhibitor/fibroblast stimulator in comparison with those from normal individuals. Our research plan is designed to investigate this substance to determine if there are other characteristics which link it to the pathogenic mechanisms involved in scleroderma. The studies will include the investigation of monocyte activation, in relation to production of this inhibitor, and the characteristics of monocytes which produce increased amounts of the IL-1 inhibitor/activator. Various substances known to activate monocytes, as well as virus infection of monocytes, will be examined to determine whether any may selectively cause monocytes to produce this inhibitor, and whether evidence relates such a substance to scleroderma. More distal areas relating to a possible role for this substance in scleroderma will also be explored. Production of IL-1, and the low m.w. IL-1 inhibitor/fibroblast stimulator will be examined in other inflammatory and fibrotic states to determine if the latter are associated with selective increases in inhibitor production. We will also examine the action of this IL-1 inhibitor on fibroblasts in considerably greater dtail, including its effect on fibroblast proliferation and secretion of collagen and glycosaminoglycans. We also plan to study its effects on other related IL-1 activities such as stimulation of collagenase production by fibroblasts. We will examine tissues to determine the presence and/or possible production of the inhibitor in involved tissues in scleroderma and other related conditions, using a specific monoclonal antibody, or oliogonuclecotide probes now being developed. Possible identity with this inhibitor with scleroderma serum factors previously described as fibroblast mitogens will also be investigated. Our long term objective is to develop methods for early diagnosis, more effective treatment, cure, or prevention of scleroderma.
