The broad purpose of this work is to further understand how microorganisms through 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 initially studied the role of complement receptor 3 (CR3, CD11b/CD18) in regulation of IL-12 production from human monocytes. We determined that signaling via CR3, which serves as a receptor for a number of infectious organisms and endogenous molecules, such as the complement fragment opsonin iC3b, suppresses the ability of human monocytes to make IL-12 in response to known IL-12 stimuli. These studies established a novel role for CR3 in regulating cell mediated immune responses via its ability to regulate the production of IL-12, and suggest that organisms that bind to CR3 in either a complement- dependent or independent fashion have evolved to take advantage of this pathway to avoid the induction of IL-12 dependent T helper 1 (Th1) immune responses that are important for host defenses. Since these initial findings, we have focused our work on understanding the mechanism and relevance of CR3-mediated suppression of IL-12 production, and on how these findings relate to other newly defined signals for the regulation of IL-12 production in humans. These studies involve defining the relevant CR3-mediated intracellular signals and their effects on transcription factors that regulate IL-12 gene transcription, determining IL-12 production from cells of patients with a genetic defect in beta2-integrin expression (leukocyte adhesion deficiency), and examining the role of CR3 activation on IL-12 production in vitro. A second aspect of this project involves the ability of molecules that signal via G-protein coupled receptors to affect the production of IL-12 from human cells. The purpose of these studies is to define endogenous factors that regulate IL-12 production during normal and abnormal immune responses in vivo, and to determine whether novel therapeutic agents for autoimmune or infectious diseases can be developed based on this information. We initially determined that cholera toxin, which activates Gs-mediated signaling can suppress IL-12 production from monocytes and dendritic cells. We now have defined a series of chemokines that can also suppress IL-12 production via a mechanism that involves the activation of Gi-mediated signaling. - Integrin, IL-12, chemokine, G-protein, cholera toxin, complement, Th1, Th2, autoimmunity, CD18 - Human Subjects
