Uncovering the mechanism of IL-4-mediated T cell survival Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/3484zk94c

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  • Although IL-4 is a well-characterized multi-functional cytokine, its role as a survival factor in T cells is not completely understood. In an attempt to uncover IL-4-mediated survival, we studied caspase activation in primary mouse T lymphocytes undergoing death by neglect, activation-induced or steroid-induced cell death. Here, we identify the executioner caspases-3, and -6, and, to a lesser extent, caspase-4 to be involved in the apoptotic process of T cells in our model, as demonstrated by a peptide inhibition assay. Furthermore, we show that IL-4 blocks caspase-3 activation in T cells undergoing all three forms of apoptosis. Western blot and flow cytometric analysis showed a substantial decrease in dexamethasoneinduced and death by neglect-induced caspase-3 activation upon IL-4 treatment, indicating IL-4 to be an important modulator of caspase-3 activity. Since a major pathway leading to caspase activation involves mitochondrial disruption and/or the release of pro-apoptotic proteins, we analyzed mitochondrial membrane potential (ΔΨₘ) in T cells undergoing various forms of apoptosis in an attempt to define the mechanism(s) by which IL-4 blocks caspase-3 activation. IL-4 treatment resulted in a reduction of mitochondrial disruption, as defined by ΔΨₘ. Moreover, in T cells derived from B ax-deficient mice, it appeared that IL-4-mediated survival involved a mechanism that does not include the modulation of the pro-apototic Bax protein. These data suggest that IL-4-mediated T cell survival involves the blockage of caspase-3 activation through a mechanism that relies on the maintenance of ΔΨₘ.
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