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  • Title: IL-2 and IL-4 mediate through two distinct kinase pathways for the activation of alphaCD3-induced activated killer cells.
    Author: Wang J, Hargrove ME, Ting CC.
    Journal: Cell Immunol; 1996 Dec 15; 174(2):138-46. PubMed ID: 8954613.
    Abstract:
    The present study has examined the role of IL-2 and IL-4 in the regulation of different kinase pathways for the generation of alphaCD3-induced activated killer cells, CD3-AK. It has previously been shown that the IL-2 promoted CD3-AK cell response is mediated through a PKC (protein kinase C)-dependent pathway, which is susceptible to PKC inhibitors and resistant to inhibitors of PTK (protein tyrosine kinase), and that IL-4 synergized with IL-2 to induce CD3-AK cells. However, the IL-4-promoted CD3-AK cell response was PKC-independent as assessed by its resistance to PKC inhibitors. These findings suggest a dichotomy in the pathways leading to CD3-AK cell generation. To further determine whether IL-4 mediated a different kinase pathway to activate the T cells, we studied its effect on protein tyrosine phosphorylation. IL-4 up-regulated protein tyrosine phosphorylation in CD3-AK cells in a dose-dependent fashion, and resulted in increased levels of a number of phosphorylated proteins. Of particular note was the increase of tyrosine phosphorylated p56(lck) and p59(fyn) in CD3-AK cells. The changes in global protein tyrosine phosphorylation were correlated with the up-regulation by IL-4 of CD3-AK cell cytolytic activity, and the production of granzyme A. alphaIL-4 specifically blocked all the effects which were induced by IL-4. The PTK inhibitor genistein inhibited the IL-4-augmented cytolytic activity of CD3-AK cells as well as the IL-4-induced augmentation of protein tyrosine phosphorylation to the basal level of CD3-AK cells cultured in IL-2 alone. Consistent with a dichotomy in pathways for IL-2- and IL-4-mediated CD3-AK generation, genistein had no effect on the generation of CD3-AK cells cultured in IL-2 alone. Thus while PKC is primarily involved in the generation of IL-2-promoted CD3-AK cells, PTK appears to be required for the regulation of IL-4-promoted CD3-AK response.
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