The effect of bryostatin 1 on human lymphocyte-mediated cytotoxicity.
We compared the effects of bryostatin 1 (BRYO), a non-tumor-promoting protein kinase C activator, and phorbol myristate acetate (PMA) on various types of lymphocyte cytotoxicity. An 18-h preincubation of lymphocytes with 10(-8) M BRYO inhibited natural killer (NK) activity but this inhibition was not statistically significant (p = 0.28). In contrast, NK activity was significantly enhanced by preincubation of lymphocytes with 10(-8) M PMA (p = 0.0012). Thus, in 13 experiments, the mean LU/10(6) was 21 +/- 12 for control cultured cells, 16 +/- 14 for BRYO cultured cells, and 40 +/- 22 for PMA cultured cells as determined in 51Cr-release assays with K562 target cells. Both BRYO and PMA inhibited lymphocyte antibody-dependent cell-mediated cytotoxicity (ADCC) such that, at a 20:1 effector-to-target ratio, control lymphocytes had a mean 49 +/- 12% specific 51Cr release of antibody-coated target cells while BRYO and PMA cultured lymphocytes had 12 +/- 6 and 8 +/- 12%, respectively, in four experiments. The reduction in ADCC was paralleled by a decrease in Fc receptor (CD16) expression as determined by immunofluorescence analysis. We assessed the ability of BRYO and PMA to induce lymphokine-activated killer (LAK) activity by culturing lymphocytes with optimally mitogenic doses of these compounds and testing for cytotoxicity of Daudi target cells. While both BRYO and PMA induced [3H]thymidine uptake, neither induced LAK activity. Furthermore, both compounds inhibited induction of LAK activity by recombinant interleukin-2 (rIL-2) in cocultures. We also analyzed the effect of BRYO and PMA on preactivated LAK effector cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Tilden
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Department of Medicine, University of Alabama, Birmingham 35294.
Kraft
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D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000943:Antigens, Differentiation / Q000378:metabolism; D054713:Bryostatins; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007783:Lactones / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018942:Macrolides; D011493:Protein Kinase C / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism; D017452:Receptors, IgG; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000943:Antigens, Differentiation; D054713:Bryostatins; D007376:Interleukin-2; D007783:Lactones; D018942:Macrolides; D011961:Receptors, Fc; D017452:Receptors, IgG; D011994:Recombinant Proteins; C046785:bryostatin 1; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate