Interleukin (IL)-11 is a multifunctional cytokine which has been shown to be important in hematopoiesis and other biological processes. The cDNA encoding IL-11 was originally isolated by the P.I. from a primate bone marrow derived stromal fibroblast cell line based on the ability of the cytokine to stimulate the proliferation of an IL-6-dependent plasmacytoma cell line. Phase I and II clinical trials demonstrated that IL-11 is an important thrombopoietic agent that can be used safely in patients with severe chemotherapy-induced thrombocytopenia. The use of IL-11 in cancer patients with thrombocytopenia has recently been approved by FDA Advisory Committee. Because of its immunomodulatory activity and ability to maintain the integrity and promote healing of the gastrointestinal mucosa, IL-11 may also reduce the severity of chemotherapy-induced mucositis and associated inflammatory complications. These biological activities have led to clinical trials for treatment of chemotherapy-induced mucositis and Crohn s disease. Based on its ability to enhance thrombopoiesis, protect gastrointestinal epithelial injury and reduce inflammatory complications, IL-11 therefore represents a multifunctional cytokine that may potentially offer several benefits in cancer therapy. One of my long term research interests has been to understand the process of how cytokine signaling correlates with biological functions and understand the mechanisms of actions of cytokines in treating human diseases. We have analyzed the signaling events mediated by IL-11 in several different cell lines. Signaling studies have resulted in the identification of several important molecules involved in IL-11 signaling and the speculation that some of these molecules may determine IL-11 biological specificity, redundancy and pleiotropy. The observations have led to the following hypotheses which will be tested in this proposal: 1) Overexpression, antisense expression and mutations of SHP-2, JAKs/Stats, IRS and gp130 proteins will affect biological functions of IL-11; (2) Structural domain requirements for different signaling molecules may vary among members within the same cytokine superfamily and in different cell types and these differences may determine their cytokine specificity, redundancy and pleiotropy; (3) The specificity of gp130 cytokines can be determined by specific signaling molecules and genes yet to be identified. To test these hypotheses, we will (1) determine the role of SHP-2, JAKs/Stats, IRS and gp130 proteins in IL-11 signaling, (2) analyze gp130 associated molecules and (3) examine the primary response genes activated by IL-11. It is anticipated that understanding of the molecular basis of cytokine signal transduction and cellular responses may lead to new modalities of treatment for both cancer and leukemia.
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