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 PKCalpha and delta 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 microM) concentration it blocks translocation of PKCdelta, diminishes DNA binding activity of AP-1 transcription factor, and attenuates cytokine production [tumor necrosis factor alpha (TNF-alpha) > interleukin-1beta (IL-1beta)]. (2) At high (50 microM) concentration it prevents translocation of PKCalpha, and subsequently inhibits ERK1/ERK2 phosphorylation, DNA binding activities of AP-1 and nuclear factor-KB transcription factors, and the production of both tested cytokines. Thus, we propose that cytosol-to-membrane translocation of PKCalpha and PKdelta isoenzymes may represent early steps in the signaling cascades that lead to TNF-alpha and IL-1beta production in human monocytes.
Kontny
E
E
Department of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland. zpatiir@warman.com
Kurowska
M
M
Szczepańska
K
K
Maśliński
W
W
D000098:Acetophenones / Q000494:pharmacology*; D000328:Adult; D001578:Benzopyrans / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C085746:rottlerin; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate