: Bacterial products invoke profuse cytokine production from mammalian leukocytes. Most of these cytokines are proinflammatory in nature and play an integral role in the innate immune response to pathogens. These cytokines include TNFalpha, IL-1,IL-6 and IL-12. In addition to these proinflammatory cytokines, leukocytes also typically produce modest amounts of antiinflammatory cytokines with the potential to dampen innate inflammatory responses. These antiinflammatory cytokines include IL-10 and TGFbeta. The regulation of cytokine production is important because the excess production of proinflammatory cytokines has been associated with endotoxic shock and with a variety of autoimmune pathologies. In the present proposal we will examine a novel way to manipulate macrophages to preferentially make antiinflammatory cytokines in response to bacterial products. We have previously demonstrated that the ligation of phagocytic receptors on macrophages can modulate cytokine production. In the present proposal we will focus our studies on the macrophage Fc-gamma receptors because they are particularly adept at influencing cytokine production. The ligation of specific macrophage Fc-gammaR efficiently turns off IL-12 transcription and induces the production of high amounts of IL-10. The IL-10 that is produced by these macrophages is biologically active and can dramatically alter macrophage physiology. Thus, the macrophage Fc-gammaRs can alter the fundamental nature of the innate response to bacterial products. In the present proposal we plan to explore the molecular nature of these alterations in cytokine production with an eye to the development of novel classes of antiinflammatory compounds that modulate macrophage cytokine responses. Specifically we will examine the molecular regulation of the transcription of IL-10 and IL-12. The nature of the signaling responses through the Fc-gammaRs and specifically the role of the common gamma chain in signaling for IL-10 upregulation will be determined. Finally, in vivo models will be developed to determine the extent to which inflammatory responses can be blunted by Fc-gammaR ligation.
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