Suppression of Antigen and Mitogen Induced Human T Lymphocyte DNA Synthesis by Bacterial Lipopolysaccharide: Mediation by Monocyte Activation and Production of Prostaglandins

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Abstract
These studies further characterize the effects of bacterial lipopolysaccharide (LPS) on circulating human mononuclear cells. Escherichia coli LPS did not induce 3H-thymidine incorporation in unseparated mononuclear cells from healthy subjects during 5 days of culture. However, in co-culture experiments, LPS 2 to 20 µg/ml suppressed the response to suboptimal concentrations of phytohemagglutinin and streptokinase-streptodornase by 36 to 84%. Depletion of adherent cells or phagocytic cells resulted in a T lymphocyte-enriched population highly responsive to stimulation by antigens and mitogens but refractory to suppression by LPS. Add-back experiments confirmed adherent cell dependence of the suppressive activity of endotoxin. Moreover, 5 × 104 adherent cells cultured with LPS for 24 hr and then washed inhibited the response of 1.5 × 105 T lymphocytes to antigen by 44 to 67%. Larger numbers of untreated adherent cells had a similar effect. Endotoxin was shown to activate monocytes under these cultural conditions by the criteria of increased attachment to plastic surfaces (by 2.0-fold) and increased release of immunoreactive prostaglandin E2 (by 6.6-fold). The prostaglandin release of cells cultured with LPS was reversed by indomethacin. Indomethacin and RO-20-5720 also blocked inhibition of lymphocyte function by large numbers of adherent cells and endotoxin-activated adherent cells. Moreover, supernatants of macrophages cultured with or without LPS suppressed T lymphocyte function; this activity was diminished when indomethacin was present during supernatant generation. These findings suggest that bacterial LPS activates human monocytes to produce prostaglandins that suppress T lymphocyte function.