The investigator notes that IL-4 regulates lymphocyte homeostasis by protecting cells from apoptosis and also by acting as a costimulant for cellular proliferation. Previous studies by this investigator demonstrated that in the IL-3-dependent myeloid progenitor cell type 32D, IL-4 signal transduction involves a member of the insulin receptor substrate (IRS) family. In preliminary studies from this application, the investigator has found that normal B-cells express low levels of IRS-2 message but none for IRS -1. Additional evidence is provided for IL -4 induced tyrosine phosphorylation of IRS -2 in small resting B- cells and in LPS or CD40 ligand stimulated blasts. This phosphorylated IRS -2 molecule co-precipitates with the p85 subunit of PI-3 kinase in both resting and activated B-cells. In contrast, phosphorylated IRS-2 was not found to be associated with Grb2 in resting B-cells, but only in those cells activated via LPS or CD40 ligand. The investigator interprets these results to indicate that polyclonal B-cell activators can alter IL-4 induced signal transduction pathways and suggests the hypothesis that the IRS/PI-3 kinase pathway is linked to the IL -4 induced protection from apoptosis, while the IRS/Grb2 pathway may be linked to proliferation. The overall goal of this application is to determine the role of IRS-mediated signaling pathways in regulating B- cell survival and proliferation.
Three specific aims are presented to approach this goal. The first is to determine the basis for IL -4 induced signaling differences in resting versus activated B-cells. The second specific aim for this application is to determine the role of IRS/PI-3 kinase and the IRS/Grb2 pathways in signaling B-cell survival and proliferation by expression of IRS-2 on splenic B-cell survival and proliferation. Collectively, the investigator hopes that the studies described in this application will increase our understanding of how IL- 4 signals, its biologic responses, and specifically how it may use the IRS family of signal transducers to serve these functions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Finerty, John F
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American National Red Cross
United States
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