Cytokines transmit signals important for communication among cells of the immune system and between cells of the immune system and other cells. Within the immune system, cytokines play a major role in B and T cell growth and differentiation, including the growth and differentiation of IgA B cells. Relevant to the proposed studies, we have previously demonstrated that interleukin-5 (IL-5) has activity as a late acting IgA B cell differentiation factor. This Project has three Specific Aims.
The first Aim i s to define the molecular mechanism by which cytokines such as IL-5 and bacterial products such as lipopolysaccharide (LPS) upregulate IgA production. In initial studies, we have established a model system for studying cytokine or LPS stimulated IgA secretion. Studies in the next Project period will define the molecular mechanisms important for the regulated expression of IgA production in this model system. Parasites and bacterial pathogens in the intestine are in contact with and invade intestinal epithelial cells. Cytokines produced by intestinal epithelial cells in response to enteric parasites and bacterial pathogens may play an important role as an early signaling system to adjacent and underlying cells of the immune system following infection.
The second Aim of this Project will be to characterize the cytokines produced by intestinal epithelial cells in response to infection with the bacterial pathogen S. dublin and the parasite G. lamblia. These studies build on our initial finding that intestinal epithelial cells constitutively produce cytokines and can be stimulated to upregulate cytokine production in response to physiologic agonists. Peyer's patches are a major site for the entry, replication and persistence of bacterial pathogens, such as Salmonella, in the intestine. Moreover, the constellation of cytokines produced by cells in Peyer's patches, as well as in the mesenteric lymph nodes in response to enteric bacterial infection can determine the hosts' susceptibility and resistance to infection, and the outcome of infection. Therefore, the third Aim of these studies is to define the role specific constellations of cytokines produced in Peyer's patches and mesenteric lymph nodes play in determining host susceptibility or resistance to infection with the enteric pathogen S. dublin. Together, these studies will provide important new information regarding the importance of intestinal epithelial cells and the intestinal mucosal immune system in host resistance to bacterial and parasitic pathogens.
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