Hydroxyurea and Zileuton Differentially Modulate Cell Proliferation and Interleukin-2 Secretion by Murine Spleen Cells: Possible Implication on the Immune Function and Risk of Pain Crisis in Patients with Sickle Cell Disease

  • Ochsner J. 2015 Fall;15(3):241-7.
Solo Kuvibidila  1 ,  Rajasekharan P Warrier  2 ,  Johnson Haynes  3 ,  Surendra B Baliga  3
Affiliations
  • 1. Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA ; Division of Research, The Research Institute for Children, Children's Hospital, New Orleans, LA.
  • 2. Department of Pediatrics, Division of Hematology/Oncology, Louisiana State University Health Sciences Center, New Orleans, LA ; Department of Pediatric Hematology/Oncology, Ochsner Clinic Foundation, New Orleans, LA ; The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA.
  • 3. Department of Pediatrics and The Sickle Cell Center, University of South Alabama College of Medicine, Mobile, AL.
PMID: 26412995
Abstract

Background: Hydroxyurea (HU) reduces major complications associated with sickle cell disease in part because of the induction of fetal Hemoglobin. However, because of its antiproliferative property, its long-term use may impair immunity. Zileuton, a derivative of HU, also induces fetal Hemoglobin and has antiinflammatory properties, a feature that can reduce the risk of sickling. Our goal was to investigate the capacity of both drugs to modulate the secretion of interleukin-2 (IL-2), a regulatory cytokine for immune responses.

Methods: Spleen cells obtained from 11 4-month-old C57BL/6 female mice were incubated without and with 10 μg/mL HU or zileuton, 2.5 μg/mL concanavalin A (ConA), 20 μg/mL phytohemagglutinin (PHA), and 50 ng/mL anti-CD3 antibody for 12-48 h. IL-2 was measured in the supernatant by enzyme-linked immunosorbent assay and cell proliferation by (3)H-thymidine uptake.

Results: While HU reduced lymphocyte proliferation in response to mitogens (P<0.05), zileuton did not. Baseline IL-2 concentration and PHA-induced IL-2 were not significantly affected by either drug. Contrary to what we expected, while HU increased IL-2 supernatant levels 1.17-fold to 6.5-fold in anti-CD3 antibody-treated cells (P<0.05), zileuton decreased them 35%-65% (P<0.05). Zileuton likely reduced IL-2 levels by inhibiting 5-lipoxygenase, hence leukotriene B4 production, an IL-2 Inducer. HU did not decrease IL-2 secretion likely because of its lack of effect on mRNA and protein synthesis.

Conclusion: Modulation of IL-2 secretion by zileuton and/or reduced lymphocyte proliferation by HU may impair the immune response of patients with sickle cell disease but may also be beneficial by attenuating inflammation independently of fetal Hemoglobin induction.

Keywords
Anemia–sickle cell; hydroxyurea; interleukin-2; mice; zileuton.
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