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.
BACKGROUND
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.


OBJECTIVE
To determine whether hydroxyurea and zileuton, a hydroxyurea derivative with antiinflammatory properties, affect IL-13 secretion.


METHODS
We measured IL-13 in the supernatant of murine spleen cells incubated without and with hydroxyurea, zileuton (10 microg/ml), concanavalin A (2.5 microg/ml), and anti-CD3 (50 ng/ml) (n=8).


RESULTS
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).


CONCLUSIONS
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.
Kuvibidila
Solo
S
Department of Pediatrics, Division of Research, Louisiana State University Health Sciences Center and the Research Institute for Children, 1542 Tulane Avenue, Box T8-1, New Orleans, LA 70112, USA. skuvib@lsuhsc.edu
Baliga
B Surendra
BS
Gardner
Renee
R
Yu
Lolie
L
Warrier
Raj
R
Velez
Maria
M
Ode
David
D
Haynes
Johnson
J
D000755:Anemia, Sickle Cell / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D005260:Female; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018793:Interleukin-13 / Q000032:analysis / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
D017077:Culture Media, Conditioned; D018793:Interleukin-13; D019010:Vascular Cell Adhesion Molecule-1; C063449:zileuton; D006918:Hydroxyurea