The broad purpose of this work is to further understand how microorganisms and vaccine adjuvants via their interaction with antigen presenting cells, such as macrophages and dendritic cells, affect the generation of T cell mediated immune responses via their ability to regulate the production of critical cytokines, such as IL-12 and IL-10. We have focused our work over the last year on 2 areas. First, we examined the mechanisms by which IL-12 production is regulated by by G-protein signaling. Ligands for certain G(i)-protein-coupled receptors (GiPCRs) potently inhibit the production of IL-12 by human monocytes. We addressed the intracellular signaling mechanisms by which this occurs using primary human cells. We identified that signaling via the PI3K and the MAP kinase JNK are essential for suppressionof IL-12 production by Gi-protein-coupled receptors, such as the C5a receptor. Importantly, these studies the essential link between Gi-signaling and PI3K signaling that is important for IL-12 regulation. These studies are important in that they demonstrate how one aspect of the immune system, Gi-signaling via chemoattractants and complement components can affect anther component, adaptive immunity via the control of IL-12 production by antigen presenting cells. Since many surface receptors signal via the PI3K pathway, these studies have also identified a possible common link between many seemingly disparate surface receptors that regulate the production of IL-12. Second, we are also exploring ways to exploit signaling pathways that regualte IL-12 and IL-23 production for the suppression of autoimmune disease. Several years ago we identified that signaling though another surface receptor, complement-receptor 3 (CD3,CD11b/CD18, Mac-1) inhibits IL-12 but not IL-10 production by human monocytes, and that antibodies to CR3 could be used to suppress IL-12 production in vitro. This has implications for understanding how pathogens that use CR3 as an receptor for entry into cells like monocytes and macrophages, have explited this pathway by preventing adequate IL-12 and Th1 responses necessary for their rapid erradication. In addition, they suggested that anti-CR3 may be used to inhibit abnormal inflammatory diseases. Over the last year we evaluated the ability of antibodies to CR3 to treat murine models of colitis and skin inflammation. We determined that anti-CR3 could be used effectively to treat inflammatory colitis and psorisiform dermatitis, indicating a possible novel approach to treatment of inflammatory bowel disease and psoriasis in humans.
