title: Interleukin-4 modulates the inflammatory response in ifosfamide-induced hemorrhagic cystitis.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Rua Cel. Nunes de Melo, 1127, 60430-270, Fortaleza, Ceará, Brazil.
authors.forename: Francisco Yuri Bulcão
authors.initials: FY
authors.lastname: Macedo
authors.forename: Lívia Talita Cajaseiras
authors.initials: LT
authors.lastname: Mourão
authors.forename: Helano Carioca
authors.initials: HC
authors.lastname: Freitas
authors.forename: Roberto C P
authors.initials: RC
authors.lastname: Lima
authors.forename: Deysi Viviana Tenazoa
authors.initials: DV
authors.lastname: Wong
authors.forename: Reinaldo Barreto
authors.initials: RB
authors.lastname: Oriá
authors.forename: Mariana L
authors.initials: ML
authors.lastname: Vale
authors.forename: Gerly Anne Casto
authors.initials: GA
authors.lastname: Brito
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Ronaldo A
authors.initials: RA
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D006470:Hemorrhage; D007069:Ifosfamide / Q000633:toxicity*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D015080:Mesna / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology*
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015080:Mesna; D007069:Ifosfamide