C<sub>2</sub>‐ceramide and C<sub>6</sub>‐ceramide inhibited priming for enhanced release of superoxide in monocytes, but had no effect on the killing of leukaemic cells by monocytes

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<jats:p>Ceramide acts as an intracellular second messenger in cellular signal transduction. We examined the effects of two cell‐permeable ceramides, C<jats:sub>2</jats:sub>‐ceramide and C<jats:sub>6</jats:sub>‐ceramide, on human monocyte functions. After monocytes were primed with lipopolysaccharide (LPS) or interferon‐<jats:italic>γ</jats:italic> (IFN‐<jats:italic>γ</jats:italic>) for 18 hr in suspension culture, they produced a high amount of superoxide (O−<jats:sub>2</jats:sub>) when triggered by phorbol myristate acetate. C<jats:sub>2</jats:sub>‐ or C<jats:sub>6</jats:sub>‐ceramide inhibited O−<jats:sub>2</jats:sub> release from monocytes primed with LPS (1 ng/ml) or IFN‐<jats:italic>γ</jats:italic> (100 U/ml), but did not affect unprimed monocytes. An analogue, C<jats:sub>2</jats:sub>‐dihydroceramide, was inactive. C<jats:sub>2</jats:sub>‐ceramide was most effective at 6 <jats:italic>μm</jats:italic>, and C<jats:sub>6</jats:sub>‐ceramide at 60 <jats:italic>μm</jats:italic>. C<jats:sub>2</jats:sub>‐ or C<jats:sub>6</jats:sub>‐ceramide at these concentrations was not toxic for monocytes, as assessed by trypan blue exclusion and by the 3‐[ 4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide (MTT) assay which measures the ability of live cells to produce formazan. C<jats:sub>2</jats:sub>‐ceramide (20 <jats:italic>μm</jats:italic>) had no effect on the killing of leukaemic cells (HL‐60 and K562 cells) by monocytes treated with IFN‐<jats:italic>γ</jats:italic>, LPS, or both for 18 hr, with killing assessed by an <jats:sup>111</jats:sup>Indium‐releasing assay. C<jats:sub>2</jats:sub>‐ceramide (20 <jats:italic>μm</jats:italic>) induced secretion of low amounts of tumour necrosis factor‐<jats:italic>α</jats:italic> (TNF‐<jats:italic>α</jats:italic>) and interleukin‐1<jats:italic>β</jats:italic> (IL‐1<jats:italic>β</jats:italic>) from the monocytes. But C<jats:sub>2</jats:sub>‐ceramide did not alter the higher secretion of TNF‐<jats:italic>α</jats:italic> or IL‐1<jats:italic>β</jats:italic> from monocytes treated with IFN‐<jats:italic>γ</jats:italic> or LPS. Thus, the cell‐permeable ceramides acted like antagonists of LPS, rather than analogues of LPS, as has been proposed. The results here showed that the signal transduction pathway for O−<jats:sub>2</jats:sub> release by monocytes differed from that for the cytolysis of leukaemic cells, and confirmed that oxygen radicals are not involved in cytolysis.</jats:p>

収録刊行物

  • Immunology

    Immunology 90 (4), 477-482, 1997-04

    Wiley

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