The IL-3 family of ligands, which include IL-3, IL-5 and GM-CSF, have been implicated in the pathogenesis of asthma. Both IL-5 and GM-CSF are expressed at elevated levels in the pulmonary tissues and secretions of patients suffering from asthma. These cytokines have been shown to play a crucial role in the growth and activation of eosinophils, mast cells, and several additional pro-inflammatory cells. Furthermore treatment with IL-5 specific antibodies has been shown to block asthma in the guinea pig model. However, the mechanism by which these cytokines mediate these effects has been poorly characterized. Recently, the IL-3 family has been shown to activate two distinct, but related signaling pathways depending on the differentiation state of the target cell. The pathway activated in immature myeloid cells employs a signal transducing factor (STF-IL3a) that is biochemically and functionally distinct from the signal transducing factor (STF-IL3b) activated in mature myeloid cells. This may provide the first mechanistic explanation of how the same cytokine can be both an essential growth factor in immature cells and have an important but distinct pro-inflammatory effect on more mature cells (eosinophils and mast cells). The genes encoding the component proteins (p77 and p80) of STF-IL3a have recently been cloned and found to be isoforms of Stat 5, a factor first described based on the ability to mediate prolactin- stimulated activation of casein genes. The components of STF-IL-3b have distinct molecular weights (p94 and p96), but also appear to be isoforms of Stat 5. The authors have hypothesized that these four proteins are the products of two distinct Stat 5-like genes. The generation of different forms of these proteins may be regulated in immature vs. mature cells.
The specific aims of this proposal are to: 1. Characterize the differential role of four Stat 5 isoforms in mediating signals for the IL-3 family of ligands. 2. Identify additional ligand specific components in the two signaling cascades activated by the IL-3 family of ligands. 3. Target the specific interactions between Stat 5 isoforms and the IL3beta receptor chain for interruption.
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