INTERLEUKIN 10 RECEPTOR COMPLEX

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DESCRIPTION (Adapted from Investigator's Abstract): The cytokine interleukin-10 (IL-10) exhibits a wide spectrum of effects on the immune system from inhibition to stimulation of various functions and cells. One receptor chain that binds IL-10 was identified and cloned (IL-10R1), however, the existence of this single receptor chain could not explain all the effects of IL-10. Accordingly, we set out to identify the second chain of the IL-10 receptor complex and were able to define and initially characterize the second chain, designated IL-10R2. Whereas each chain alone cannot impart full responsiveness of cells to IL-10, the combination of both chains can. With the identification of the second chain, IL-10R2, a number of questions regarding the functional IL-10 receptor complex can now be approached. This proposal is designed to answer questions about the role of the IL-10R2 chain in mediating IL-10 effects in the immune system and in some cancers. The overall hypothesis underlying this proposal is that both receptor chains are required for function of IL-10. The results will enable us to understand how IL-10 functions in the immune system. In addition, since Epstein- Barr virus (EBV) produces a viral homolog of IL-10 designated vIL-10, we will examine the differences in activity between IL-10 and vIL-10 that should provide insight into the role of vIL-10 in EBV-related malignancies. Specific aims of this study are: 1) the role of the Hu- IL-10R2 chain in IL-10 function; 2) determine how IL-10 inhibits functions of other cytokines; 3) regulation of the IL-10R2 gene; 4) determine regulation of the mRNAs of IL-10 and the IL-10 receptor chains (IL-10R1 and IL-10R2); 5) define the differences in function of cellular and viral IL-10. Our results should establish the role of the second chain in IL-10 receptor function, enhance our understanding of how IL-10 functions, and provide insight into the role of the EBV protein vIL-10 in EBV-induced cancers. Furthermore, because IL-10 is an important immunosuppressive cytokine in immune function such as in development of T-cell subsets, the knowledge gained should help us understand the mechanisms by which IL-10 mediates immunosuppression.