Human T lymphocyte activation by tumor promoters: role of protein kinase C.
Protein kinase C (PKC) has a major role in a ligand-receptor-mediated signal transduction system in a variety of cell types including T lymphocytes. One of the early phenotypic changes associated with T cell activation is the expression of cell surface receptors for interleukin 2 (IL 2). To test the role of PKC in regulation of IL 2 receptor (IL 2-R) expression and T cell activation in general, we used tumor promoters (TP) as modulators of PKC and compared their effects on intact human T cells and on the enzymatic activity of T cell-derived PKC in a cellfree system. In T cells, the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced IL 2-R expression and proliferation associated with cytosol-to-membrane PKC translocation. A dose of TPA (1 to 4 ng/ml) that induced about 50% of the maximal activation of PKC in the enzymatic assay also induced half-maximal effects on cell proliferation, IL 2-R expression, and PKC redistribution in intact T cells. Structure-function studies with several phorbol ester analogs and non-phorbol ester TP directly correlated tumor promotion activity with the ability to activate PKC and induce IL 2-R. An inhibitor of PKC, chlorpromazine, was found to suppress TPA-mediated proliferation and IL 2-R expression, and inhibited T cell-derived PKC by competing with the phospholipid. Ca2+ ionophore, which synergizes with TPA in induction of T cell proliferation, facilitated the TPA-induced PKC translocation to the membrane. The results thus demonstrate a direct correlation between the effects of various chemicals on: subcellular redistribution of PKC in T cells; induction of T cell proliferation and IL 2-R expression; and activation of T cell-derived PKC in vitro. These data provide further support for the role of PKC in transduction of activation signals in T cells and in regulation of IL 2-R expression.
D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008565:Membrane Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis; D015375:Receptors, Interleukin-2; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D002273:Carcinogens; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D002746:Chlorpromazine