Rottlerin, a PKC isozyme-selective inhibitor, affects signaling events and cytokine production in human monocytes

The implication of select protein kinase C (PKC) isoenzymes in cytokine production by human monocytes was investigated using an isozyme-selective inhibitor of PKC, rottlerin. We found that lipopolysaccharide (LPS) triggers cytosol-to-membrane translocation of PKCα and δ isoenzymes, whereas phorbol ester (PMA) induces translocation of several PKC isoforms. Moreover, we show that in LPS- and PMA-stimulated monocytes rottlerin affects several cellular responses. (1) At low (15 μM) concentration it blocks translocation of PKCδ, diminishes DNA binding activity of AP-1 transcription factor, and attenuates cytokine production [tumor necrosis factor α (TNF-α) > interleukin-1β (IL-1β)]. (2) At high (50 μM) concentration it prevents translocation of PKCα, and subsequently inhibits ERK1/ERK2 phosphorylation, DNA binding activities of AP-1 and nuclear factor-κB transcription factors, and the production of both tested cytokines. Thus, we propose that cytosol-to-membrane translocation of PKCα and PKδ isoenzymes may represent early steps in the signaling cascades that lead to TNF-α and IL-1β production in human monocytes. J. Leukoc. Biol. 67: 249–258; 2000.