Selective Activation of Specific PKC Isoforms Dictating the Fate of CD14R(+) Monocytes Towards Differentiation or Apoptosis

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-alpha/beta(1) selective inhibitor), not anilinemonoindolylmaleimide [a PKC-beta inhibitor (PKC-beta 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-beta inh., not Go6976, prevents the cells from serum deprivation-induced cell apoptosis. Although the membrane translocation of conventional PKC-alpha, beta(1), and beta(2) isoforms was observed in the H-PMA-treated CD14(+) monocytes, only PKC-beta(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-alpha or PKC-beta(1) induces the differentiation of CD14(+) monocytes into MDMs or dendritic cells (MoDCs), respectively, the results in this study further demonstrate that PKC-beta(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. J. Cell. Physiol. 226: 122-131, 2010. (C) 2010 Wiley-Liss, Inc.