: The immune response is a well tuned process. Although it is important for the immune system to mount a proper immune response to any pathological condition it is even more important to timely inhibit it. An over exaggerated immune response is destructive for the immune system. Several mechanisms are involved in regulating and balancing of the immune response. One of these mechanisms is expression of cytokines possessing immunosuppressive activities such as interleukin-10 (IL-10). Five new ligands with limited sequence homology to IL-10 have been identified. There is a body of evidence suggesting that these new cytokines may share several immunosuppressive activities of IL-10 and may be linked to asthma and allergy. Cytokines exert their actions through the binding to specific cell surface receptors that results in the activation of cytokine-specific signal transduction pathways. The active IL-10 receptor complex consists of two chains, IL-10R1 and IL-10R2. Several new receptors with homology to the IL 10 receptor chains have been identified. One of these receptors, designated CRF2-9, binds IL-TIF, one of new IL-10 homologs. Based on preliminary experiments, on structure-functional analysis of new ligands receptors and also on current knowledge of cytokine-receptor complexes, the functional IL-TIF receptor complex should consist of two receptor chains, the ligand-binding and signal-transducing CRF2-9 chain and a second accessory chain, designated IL-TIFR2, that is likely to be identical to the IL-10R2 chain. Knowledge of a receptor for a particular cytokine provide initial information about possible signal transduction cascades that can be a first step in the discovery of functions and activities of this cytokine. The proposed project aimed to characterize the functions and activities of IL-TIF and its receptor complex.
The specific aims of the project are: to characterize CRF2-9 as a ligand-binding chain for IL-TIF and to study its expression and ligand-receptor interaction; to determine the second chain of the IL-TIF receptor complex and assemble the functional IL-TIF receptor complex; to study IL-TIF-induced signal transduction events and correlating them with biological activities and assigning them to different regions of the CRF2-9 intracellular domain. The long-term goal of this project is to obtain new knowledge that will improve our understanding of mechanisms that regulate proper functioning of the immune system.
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