Pathogenic Th1-type immune responses to self-antigens are thought to play an essential role in a number of organ-specific autoimmune diseases. However, recent developments in animal models of multiple sclerosis, Crohn's disease, and rheumatoid arthritis, suggest that IL-17 producing T cells (ThlL-17) rather than the IFNg-producing Th1 cells are the most relevant participants in autoimmunity. Activated antigen-presenting cells (ARC) control the development of Th1 effectors through IL-12p70 release, and of ThlL-17 through IL- 23. In contrast to most ARC activators that induce both IL-23 and IL-12, we identified PGE2 as an inducer of IL-23 at the expense of IL-12p70. The central hypothesis in this proposal is that PGE2 released in inflammatory conditions promotes the expression and production of IL-23, while reducing IL-12p70 release from dendritic cells and microglia, and induces the subsequent generation and/or proliferation of ThlL-17. We propose that, through the IL-23-->IL-17 axis, PGE2 contributes to the maintenance of an autoimmune-prone environment in the affected tissues.
In Specific Aim 1 we propose to characterize dendritic cells (DC) and microglia (MG) exposed to or generated in the presence of PGE2 in terms of IL-23/IL-12 production and to assess their in vitro and in vivo capacity to generate ThlL-17 cells.
Specific Aim 2 is focused on the PGE2- induced signaling in DC and the identification of the relevant signaling molecules and transcription factors involved in the PGE2 regulation of p19, p40, and p35 gene transcription.
In Specific Aim 3 we propose to evaluate the role of PGE2 in vivo in two models of autoimmune diseases, the collagen-induced arthritis and the experimental autoimmune encephalomyelitis by assessing clinical symptoms, the relevant histopathology, the development of IL-17 producing T cells, and the cytokine profile in the affected tissues and in the peripheral lymphoid organs. The identification of the molecular and cellular factors involved in the generation, activation, and maintenance of IL-23-producing APC and of pathogenic ThlL-17 will have a significant impact on our understanding and intervention in autoimmune diseases. The ultimate goal for the clarification of the molecular mechanisms involved in the PGE2 control of the IL-23/IL-12 balance and for the identification of the functional PGE2 receptors on DCs and microglia is the development of new therapeutic avenues in autoimmunity. ? ? ?
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