The monocyte-macrophage series has been shown to be a site of synthesis of several of the complement (C components). Local production of C proteins by macrophages might provide initial response to tissue injury or microbial invasion by providing a mechanism fo recruiting intravascular hormonal and cellular mediators of host defense. The purpose of the experiments in this proposal is to examine the regulation of synthesis of C components in mononuclear phagocytes by products of the inflammatory response likely to be present at a local site of inflammation. The mechanism of action of two substances, gamma-interferon (IFN) and lipopolysacchride (LPS) that are known to stimulate production of C by human peripheral blood monocyte-derived macrophages, will be studied. Each of these stimuli will be more thoroughly defined and the mechanism of the stimulation will be explored by analysis of the molecular biology of synthesis of C proteins. For these experiments the complementary DNA (cDNA) for C2 and C3, the proteins stimulated by the IFN and LPS, respectively, will be utilized. The C2 cDNA has been isolated by Dr. Harvey Colten and coworkers and will be available for use in these experiments. The C3 cDNA will be isolated during a sabbatical in the first year of the grant. Both lymphokine and LPS stimulate macrophages in numerous ways other than just increasing the production of C proteins. In-depth study of the mechanisms responsible for stimulation in production of C proteins may lead to an understanding of the basic process involved in alteration of macrophage function. An understanding of the mechanisms of the macrophages response to these compounds may suggest ways to modulate the response to these compounds, and provide a basis for ways to reduce inflammation or enhance its resolution in diseases such as a rheumatiod arthritis, where local production of C may play a role in the disease process.
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