, Volume 35, Issue 1, pp 297–307 | Cite as

Interleukin-4 Modulates the Inflammatory Response in Ifosfamide-Induced Hemorrhagic Cystitis

  • Francisco Yuri Bulcão Macedo
  • Lívia Talita Cajaseiras Mourão
  • Helano Carioca Freitas
  • Roberto C. P. Lima-Júnior
  • Deysi Viviana Tenazoa Wong
  • Reinaldo Barreto Oriá
  • Mariana L. Vale
  • Gerly Anne Casto Brito
  • Fernando Q. Cunha
  • Ronaldo A. Ribeiro


We investigated whether interleukin-4 (IL-4) is present and capable of reducing inflammatory changes seen in ifosfamide-induced hemorrhagic cystitis. Male Swiss mice were treated with saline or ifosfamide alone or ifosfamide with the classical protocol with mesna and analyzed by changes in bladder wet weight (BWW), macroscopic and microscopic parameters, exudate, and hemoglobin quantification. In other groups, IL-4 was administered intraperitoneally 1 h before ifosfamide. In other experimental groups, C57BL/6 WT (wild type) and C57BL/6 WT IL-4 (−/−) knockout animals were treated with ifosfamide and analyzed for changes in BWW. Quantification of bladder IL-4 protein by ELISA in control, ifosfamide-, and mesna-treated groups was performed. Immunohistochemistry to tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) as well as protein identification by Western blot assay for inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was carried out on ifosfamide- and IL-4-treated animals. In other experimental groups, antiserum against IL-4 was given 30 min before ifosfamide. In IL-4-treated animals, the severity of hemorrhagic cystitis was significantly milder than in animals treated with ifosfamide only, an effect that was reverted with serum anti-IL-4. Moreover, knockout animals for IL-4 (−/−) exhibit a worse degree of inflammation when compared to C57BL/6 wild type. Exogenous IL-4 also attenuated TNF-α, IL-1β, iNOS, and COX-2 expressions in ifosfamide-treated bladders. IL-4, an anti-inflammatory cytokine, attenuates the inflammation seen in ifosfamide-induced hemorrhagic cystitis.


IL-4 ifosfamide bladder hemorrhagic cystitis TNF-α IL-1β iNOS COX-2 



The authors gratefully acknowledge the technical assistance of Maria Silvandira Freire, José Ivan Rodrigues, and Jand Venes Medeiros from FM-UFC-CE and Arturo Rivera from University of Miami, USA and also would like to thank the National Research Council of Brazil (CNPq) and Fundação Cearense de Amparo a Pesquisa (FUNCAP), Ceará-Brazil, for the financial support.

Financial Support

This project has received grants from National Research Council of Brazil (CNPq), CAPES, and Fundação Cearense de Amparo à Pesquisa (FUNCAP), Ceará-Brazil.

Conflict of Interests



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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Francisco Yuri Bulcão Macedo
    • 1
  • Lívia Talita Cajaseiras Mourão
    • 1
  • Helano Carioca Freitas
    • 1
  • Roberto C. P. Lima-Júnior
    • 1
  • Deysi Viviana Tenazoa Wong
    • 1
  • Reinaldo Barreto Oriá
    • 2
  • Mariana L. Vale
    • 1
  • Gerly Anne Casto Brito
    • 2
  • Fernando Q. Cunha
    • 3
  • Ronaldo A. Ribeiro
    • 1
    • 4
  1. 1.Department of Physiology and Pharmacology, Faculty of MedicineUniversidade Federal do CearáFortalezaBrazil
  2. 2.Department of Morphology, Faculty of MedicineUniversidade Federal do CearáFortalezaBrazil
  3. 3.Department of Pharmacology, School of Medicine of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil
  4. 4.Department of Clinical OncologyCancer Institute of CearáFortalezaBrazil

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