Interleukin-11 (IL-11) is a pleiotropic cytokine which has been shown to exhibit great clinical potential as a tool for the management and treatment of myelosuppressive syndrome caused by a great variety of conditions including cancer chemotherapy, physical and environmental factors. Although IL-11 has the potential to emerge as a clinical tool to treat bone marrow suppression, neutropenia and agranulocytosis associated radiation and chemotherapy, little is known about the mechanism by which it regulates hematopoietic progenitor cell growth and differentiation. The goal of this proposal is to understand how the binding of IL-11 to its receptor(s) leads to stimulation of expression of genes associated with erythroid and myeloid proliferation and differentiation. IL-11-R activation by IL-11 has been demonstrated to stimulate tyrosine phosphorylation of key signal transduction molecules and cause induction of expression of c-jun and c-fos mRNA. In addition, increases in levels of PK-C proteins occur in response to IL-11. These effects were associated with stimulation of leukemic cell growth by IL-11. In this proposal, we will (I) examine whether IL-11 regulates growth and differentiation of late erythroid and myeloid progenitor cells; (2) identify some of the key signal transduction molecules which mediate IL- 11 signaling to the nucleus and (3) determine whether IL-11 activates fos, jun and c-myc mRNA and protein synthesis. These studies will be conducted with cells grown in either conventional tissue culture incubators or NASA's ground-base bioreactors. The knowledge which will be obtained from this project will facilitate the clinic~1 evaluation of IL-11 for generation of normal functional tissues which can be utilized in the treatment of human diseases including cancer. The information can also be used to design drugs to block the neoplastic effects of IL-11.
