title: Selective activation of specific PKC isoforms dictating the fate of CD14(+) monocytes towards differentiation or apoptosis.
abstract: In this study, phorbol-12-myristate-13-acetate (PMA) at low concentrations (<10 nM; L-PMA) induces the differentiation of CD14(+) monocytes into monocyte-derived macrophages (MDMs) while PMA at high concentrations (>100 nM; H-PMA) causes the apoptosis of these cells. The pre-treatment with Go6976 (a PKC-α/β(1) selective inhibitor), not anilinemonoindolylmaleimide [a PKC-β inhibitor (PKC-β inh.)], significantly (P < 0.05) reduces the L-PMA-induced generation of MDMs in the cultured CD14(+) monocytes. On the other hand, either of the above two PKC inhibitors is capable of suppressing the H-PMA-induced apoptosis of CD14(+) monocytes. However, only the inclusion of PKC-β inh., not Go6976, prevents the cells from serum deprivation-induced cell apoptosis. Although the membrane translocation of conventional PKC-α, β(1), and β(2) isoforms was observed in the H-PMA-treated CD14(+) monocytes, only PKC-β(2) exhibits a mitochondrial translocation activity among those PKCs responsive to H-PMA treatment. Moreover, the activation of DEVD-dependent caspases (DEVDase) was also detected in the H-PMA-treated CD14(+) monocytes, indicating the involvement of a caspase-dependent signaling pathway in the H-PMA-induced cell apoptosis of CD14(+) monocytes. Together with our previous findings that the selective activation of PKC-α or PKC-β(1) induces the differentiation of CD14(+) monocytes into MDMs or dendritic cells (MoDCs), respectively, the results in this study further demonstrate that PKC-β(2) activation is responsible for relaying the apoptotic signal to intrinsic mitochondria-dependent caspase signaling cascades in the CD14(+) monocytes. It is likely that the selective activation of specific PKC isoforms provides a new strategy to manipulate the differential cell fate commitment of multipotent CD14(+) monocytes towards apoptosis or differentiation into MDMs, MoDCs, and other cell types.
authors.affiliation: School of Pharmacy, Taipei Medical University (TMU), Taipei, Taiwan, ROC.
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Lin
authors.forename: Sy-Jye
authors.initials: SJ
authors.lastname: Leu
authors.forename: Huei-Mei
authors.initials: HM
authors.lastname: Huang
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Tsai
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology* / Q000502:physiology*; D010703:Phorbol Esters / Q000494:pharmacology; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018950:Lipopolysaccharide Receptors; D010703:Phorbol Esters; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; C008874:phorbol-12,13-diacetate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C; D020169:Caspases