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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.