title: Protein kinase C has both stimulatory and suppressive effects on macrophage superoxide production.
abstract: Unlike resident peritoneal macrophages (RPM) or tumor necrosis factor alpha (TNF alpha)-primed bone marrow-derived macrophages (BMM), unprimed BMM do not generate superoxide in response to the protein kinase C (PKC) activator, phorbol myristate acetate (PMA). However, these cells do contain significant levels of PKC activity. In contrast to PMA, zymosan induces the generation of superoxide in unprimed BMM, as well as in TNF alpha-primed BMM and RPM. Staurosporine, a potent PKC inhibitor, failed to affect the zymosan-induced production of superoxide by unprimed and TNF alpha-primed BMM and RPM, in spite of substantial inhibition of PMA-induced superoxide production by the primed BMM and RPM. However, when PKC was depleted from unprimed BMM by prolonged (24 h) treatment with phorbol dibutyrate (PdBt) (10(-7) M) the ability of zymosan to induce the production of superoxide was greatly diminished. Such a result could be interpreted as suggesting a role for PKC in the zymosan-induced response, a conclusion which contrasts with the inhibitor data. However, PKC depletion, in this case, is achieved via the PdBt-induced activation of PKC. It is thus possible that it is the initial activation of PKC, rather than its depletion, that suppresses superoxide production. Consistent with this interpretation, the co-stimulation of unprimed BMM with both zymosan and PMA resulted in a reduced superoxide release compared to zymosan alone. The activation of PKC therefore appears to have a suppressive effect on the generation of superoxide by unprimed cells. We thus conclude that PKC is not required for zymosan-induced superoxide production by either primed or unprimed macrophages and suggest that PKC may be involved in regulatory mechanisms restricting superoxide production by macrophages. However, since PMA alone can initiate the release of superoxide from primed BMM and RPM, it would appear that PKC can mediate both stimulatory and suppressive signals for macrophage superoxide production.
authors.affiliation: University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: W A
authors.initials: WA
authors.lastname: Phillips
authors.forename: M
authors.initials: M
authors.lastname: Croatto
authors.forename: N
authors.initials: N
authors.lastname: Veis
authors.forename: J A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007457:Iodine Radioisotopes; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D019311:Staurosporine; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015054:Zymosan / Q000493:pharmacokinetics
chemical_list: D000470:Alkaloids; D016207:Cytokines; D004731:Endotoxins; D007295:Inositol Phosphates; D007457:Iodine Radioisotopes; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D015240:Phorbol 12,13-Dibutyrate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015054:Zymosan; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate