Apoptosis and the rapid clearance of apoptotic cells by professional phagocytes are normal and coordinated processes that ensure controlled cell growth with non-pathological outcomes. Defects in clearance of apoptotic cells have serious consequences by engendering persistent self-antigens and triggering the production of proinflammatory cytokines, resulting in the generation of autoreactive lymphocytes that drive autoimmune disorders. Phosphatidylserine (PS) exposed on dying cells and its interaction with certain phagocytic receptors are essential for the uptake of apoptotic cells by phagocytes. Interleukin-12 (IL-12) is a proinflammatory cytokine produced by phagocytic cells and plays a critical role in the activation and function of antigen-presenting cells and effector lymphocytes during microbial infection. Interleukin-10 (IL-10) is a pivotal homeostatic regulator of immune reactivity. Both IL-12 and IL-10 have been strongly implicated as effector cytokines in the pathogenesis of autoimmune disorders. The production of IL-12 and IL-10 by phagocytic and antigen-presenting cells is regulated in opposite manners following the ingestion of apoptotic cells. How apoptotic cell-derived signals regulate IL-12 and IL-10 production is not understood. Recent evidence generated by our group indicates that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression through a novel zinc finger transcriptional repressor, GC-BP, and in the activation of IL-10 expression at the transcriptional level while it inhibits IL-12 p40 post-transcriptionally. We propose to elucidate the molecular mechanisms that control the cytokine responses during phagocyte-mediated clearance of apoptotic cells. I. To investigate how apoptotic cell-derived signals regulate the synthesis of IL-12 p40 at post- transcriptional levels. II. To investigate the expression, activation and function of the transcription repressor GC-BP during phagocytosis of apoptotic cells. III. To investigate the transcriptional mechanisms whereby IL-10 gene expression is regulated during phagocytosis of apoptotic cells. The long-term goal of this project is to understand the regulation of cytokine production in normal and pathological processes of dead cell removal. The knowledge gained will be beneficial to efforts to control dysregulated host responses in infection, autoimmunity, graft-versus-host disease, and cancer.
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