Differential effects of hydroxyurea and zileuton on interleukin-13 secretion by activated murine spleen cells: Implication on the expression of vascular cell adhesion molecule-1 and vasoocclusion in sickle cell anemia

Interleukin-13 (IL-13), a TH2 cytokine, upregulates the expression of vascular cell adhesion molecule-1 on endothelial cells, a factor involved in vasoocclusion in sickle cell disease (SCD). Hydroxyurea improves clinical status of SCD patients in part by induction of fetal hemoglobin. Its effect on IL-13 secretion has not been investigated. To determine whether hydroxyurea and zileuton, a hydroxyurea derivative with antiinflammatory properties, affect IL-13 secretion. We measured IL-13 in the supernatant of murine spleen cells incubated without and with hydroxyurea, zileuton (10 μg/ml), concanavalin A (2.5 μg/ml), and anti-CD3 (50 ng/ml) ( n = 8). Hydroxyurea and zileuton do not affect baseline IL-13 secretion. Unexpectedly, hydroxyurea increases IL-13 levels above baseline (120%, 216.5%, [ p < 0.05] after 24 h and 48 h, respectively) in lymphocytes activated by anti-CD3, while zileuton reduces them by 59%–78% ( p < 0.005). In lymphocytes activated by concanavalin A, hydroxyurea and zileuton reduce IL-13 secretion by 24–36% and 50–87%, respectively ( p < 0.05). Hydroxyurea, but not zileuton, significantly inhibits spleen cell proliferative responses to mitogens ( p < 0.005). Data suggest that hydroxyurea up-regulates IL-13 secretion in anti-CD3-activated lymphocytes through gene activation but not by altered cell proliferation. Increased IL-13 secretion may contribute to unresponsiveness of certain SCD patients to hydroxyurea. The potential benefit of zileuton in the management of vasoocclusion is discussed.