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Published in: Inflammation 1/2012

01-02-2012

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

Authors: 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

Published in: Inflammation | Issue 1/2012

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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.
Literature
1.
go back to reference Higgs, D., C. Nagy, and L.H. Einhorn. 1989. Ifosfamide: a clinical review. Seminars in Oncology Nursing 5: 70–77.PubMedCrossRef Higgs, D., C. Nagy, and L.H. Einhorn. 1989. Ifosfamide: a clinical review. Seminars in Oncology Nursing 5: 70–77.PubMedCrossRef
2.
go back to reference Dechant, K.L., R.N. Brogden, T. Pilkington, et al. 1991. Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 42: 428–467.PubMedCrossRef Dechant, K.L., R.N. Brogden, T. Pilkington, et al. 1991. Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 42: 428–467.PubMedCrossRef
3.
go back to reference Macedo, F.Y., F. Baltazar, L.C. Mourao, et al. 2008. Induction of COX-2 expression by acrolein in the rat model of hemorrhagic cystitis. Experimental and Toxicologic Pathology 59: 425–430.PubMedCrossRef Macedo, F.Y., F. Baltazar, L.C. Mourao, et al. 2008. Induction of COX-2 expression by acrolein in the rat model of hemorrhagic cystitis. Experimental and Toxicologic Pathology 59: 425–430.PubMedCrossRef
4.
go back to reference Brock, N., and J. Pohl. 1983. The development of mesna for regional detoxification. Cancer Treatment Reviews 10: 33–43.PubMedCrossRef Brock, N., and J. Pohl. 1983. The development of mesna for regional detoxification. Cancer Treatment Reviews 10: 33–43.PubMedCrossRef
5.
go back to reference Scheulen, M.E., N. Niederle, K. Bremer, et al. 1983. Efficacy of ifosfamide in refractory malignant diseases and uroprotection by mesna: results of a clinical phase II study with 151 patients. Cancer Treatment Reviews 10: 93–101.PubMedCrossRef Scheulen, M.E., N. Niederle, K. Bremer, et al. 1983. Efficacy of ifosfamide in refractory malignant diseases and uroprotection by mesna: results of a clinical phase II study with 151 patients. Cancer Treatment Reviews 10: 93–101.PubMedCrossRef
6.
go back to reference Shulman, L.N. 1993. The biology of alkylating-agent cellular injury. Hematology/Oncology Clinics of North America 7: 325–335.PubMed Shulman, L.N. 1993. The biology of alkylating-agent cellular injury. Hematology/Oncology Clinics of North America 7: 325–335.PubMed
7.
go back to reference Vieira, M.M., G.A. Brito, J.N. Belarmino-Filho, F.Y. Macedo, et al. 2003. Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis. International Journal of Urology 10: 595–602.PubMedCrossRef Vieira, M.M., G.A. Brito, J.N. Belarmino-Filho, F.Y. Macedo, et al. 2003. Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis. International Journal of Urology 10: 595–602.PubMedCrossRef
8.
go back to reference Lima, M.V.A., F.V. Ferreira, F.Y.B. Macedo, and R.A. Ribeiro. 2007. Histological changes in bladders of patients submitted to ifosfamide based chemotherapy even with mesna prophylaxis. Cancer Chemotherapy and Pharmacology 59: 643–650.PubMedCrossRef Lima, M.V.A., F.V. Ferreira, F.Y.B. Macedo, and R.A. Ribeiro. 2007. Histological changes in bladders of patients submitted to ifosfamide based chemotherapy even with mesna prophylaxis. Cancer Chemotherapy and Pharmacology 59: 643–650.PubMedCrossRef
9.
go back to reference Ribeiro, R.A., H.C. Freitas, M.C. Campos, et al. 2002. Tumor necrosis factor-α and interleukin-1 β mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice. Journal d’Urologie 176: 2229–2234. Ribeiro, R.A., H.C. Freitas, M.C. Campos, et al. 2002. Tumor necrosis factor and interleukin-1 β mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice. Journal d’Urologie 176: 2229–2234.
10.
go back to reference Souza-Filho, M.V.P., M.V.A. Lima, M.M.L. Pompeu, et al. 1997. Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. The American Journal of Pathology 150: 247–256. Souza-Filho, M.V.P., M.V.A. Lima, M.M.L. Pompeu, et al. 1997. Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. The American Journal of Pathology 150: 247–256.
11.
go back to reference Macedo, F.Y., F. Baltazar, P.R. Almeida, F. Távora, F.V. Ferreira, F.C. Schmitt, G.A. Brito, and R.A. Ribeiro. 2008. Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats. Journal of Cancer Research and Clinical Oncology 134: 19–27.PubMedCrossRef Macedo, F.Y., F. Baltazar, P.R. Almeida, F. Távora, F.V. Ferreira, F.C. Schmitt, G.A. Brito, and R.A. Ribeiro. 2008. Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats. Journal of Cancer Research and Clinical Oncology 134: 19–27.PubMedCrossRef
12.
go back to reference Lord, C.J.M., and J.R. Lamb. 1996. TH2 cells in allergic inflammation: a target of immunotherapy. Clinical and Experimental Allergy 26: 756–765.PubMedCrossRef Lord, C.J.M., and J.R. Lamb. 1996. TH2 cells in allergic inflammation: a target of immunotherapy. Clinical and Experimental Allergy 26: 756–765.PubMedCrossRef
13.
go back to reference Tunon de Lara, J.M., Y. Okayama, A.R. Mceuen, et al. 1994. Release and inactivation of interleukin-4 by mast cells. Cells and cytokines in lung inflammation. Annals of the New York Academy of Sciences 725: 50–58.PubMedCrossRef Tunon de Lara, J.M., Y. Okayama, A.R. Mceuen, et al. 1994. Release and inactivation of interleukin-4 by mast cells. Cells and cytokines in lung inflammation. Annals of the New York Academy of Sciences 725: 50–58.PubMedCrossRef
14.
go back to reference Vannier, E., M.C. Miller, and C.A. Dinarello. 1992. Coordinated anti-inflammatory effects of interleukin4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist. Proceedings of the National Academy of Science 89: 4076–4080.CrossRef Vannier, E., M.C. Miller, and C.A. Dinarello. 1992. Coordinated anti-inflammatory effects of interleukin4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist. Proceedings of the National Academy of Science 89: 4076–4080.CrossRef
15.
go back to reference Seitz, M., P. Loetscher, B. Dewald, H. Towbin, M. Ceska, and M. Baggiolini. 1994. Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins, and prostaglandin E by rheumatoid and osteoarthritic synoviocytes-regulation by IFN-γ and IL-4. Journal of Immunology 152: 2060–2065. Seitz, M., P. Loetscher, B. Dewald, H. Towbin, M. Ceska, and M. Baggiolini. 1994. Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins, and prostaglandin E by rheumatoid and osteoarthritic synoviocytes-regulation by IFN-γ and IL-4. Journal of Immunology 152: 2060–2065.
16.
go back to reference Endo, T., F. Ogushi, and S. Saburo. 1996. LPS-dependent cyclooxygenase-2 induction in human monocytes is down-regulated by IL-13, but not by IFN-γ. Journal of immunology 156: 2240–2246. Endo, T., F. Ogushi, and S. Saburo. 1996. LPS-dependent cyclooxygenase-2 induction in human monocytes is down-regulated by IL-13, but not by IFN-γ. Journal of immunology 156: 2240–2246.
17.
go back to reference Malley, S.E., and M.A. Vizzard. 2002. Changes in urinary bladder cytokine mRNA and protein after cyclophosphamide-induced cystitis. Physiological Genomics 9: 5–13.PubMed Malley, S.E., and M.A. Vizzard. 2002. Changes in urinary bladder cytokine mRNA and protein after cyclophosphamide-induced cystitis. Physiological Genomics 9: 5–13.PubMed
18.
go back to reference Gray, K.J., U.H. Engelmann, E.H. Johnson, et al. 1986. Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy. Journal d'Urologie 133: 497–500. Gray, K.J., U.H. Engelmann, E.H. Johnson, et al. 1986. Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy. Journal d'Urologie 133: 497–500.
19.
go back to reference Hsu, S.M., and L. Raine. 1981. Protein A, avidin, and biotin in immunohistochemistry. The Journal of Histochemistry and Cytochemistry 29: 1349–1353.PubMedCrossRef Hsu, S.M., and L. Raine. 1981. Protein A, avidin, and biotin in immunohistochemistry. The Journal of Histochemistry and Cytochemistry 29: 1349–1353.PubMedCrossRef
20.
go back to reference Fenton, M.J., J.A. Buras, and R.P. Donelly. 1992. IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes. Journal of Immunology 149: 1283–1288. Fenton, M.J., J.A. Buras, and R.P. Donelly. 1992. IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes. Journal of Immunology 149: 1283–1288.
21.
go back to reference Cunha, F.Q., S. Moncada, and F.Y. Liew. 1992. Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-gamma in murine macrophages. Biochemical and Biophysical Research Communications 182: 1155–1159.PubMedCrossRef Cunha, F.Q., S. Moncada, and F.Y. Liew. 1992. Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-gamma in murine macrophages. Biochemical and Biophysical Research Communications 182: 1155–1159.PubMedCrossRef
22.
go back to reference Mota, J.M., G.A. Brito, R.T. Loiola, F.Q. Cunha, and R.A. Ribeiro. 2007. Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis. International Brazilian Journal of Urology 33: 704–710.PubMedCrossRef Mota, J.M., G.A. Brito, R.T. Loiola, F.Q. Cunha, and R.A. Ribeiro. 2007. Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis. International Brazilian Journal of Urology 33: 704–710.PubMedCrossRef
23.
go back to reference Trepicchio, W.L., M. Bozza, G. Pedneault, and A.J. Dorner. 1996. Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production. Journal of Immunology 157: 3627–3634. Trepicchio, W.L., M. Bozza, G. Pedneault, and A.J. Dorner. 1996. Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production. Journal of Immunology 157: 3627–3634.
24.
go back to reference Smaldone, M.C., Y. Vodovotz, V. Tyagi, D. Barclay, B.J. Philips, N. Yoshimura, M.B. Chancellor, and P. Tyagi. 2009. Multiplex analysis of urinary cytokine levels in rat model of cyclophosphamide-induced cystitis. Urology 73(2): 421–426.PubMedCrossRef Smaldone, M.C., Y. Vodovotz, V. Tyagi, D. Barclay, B.J. Philips, N. Yoshimura, M.B. Chancellor, and P. Tyagi. 2009. Multiplex analysis of urinary cytokine levels in rat model of cyclophosphamide-induced cystitis. Urology 73(2): 421–426.PubMedCrossRef
25.
go back to reference Nishisaka, F., S. Sohen, H. Fukuoka, Y. Okamoto, M. Matukawa, et al. 2001. Interleukin-4 reversed the interleukin-1-inhibited proteoglycan synthesis through the inhibition of NO release: a possible involvement of intracellular calcium ion. Pathophysiology 7(4): 289–293.PubMedCrossRef Nishisaka, F., S. Sohen, H. Fukuoka, Y. Okamoto, M. Matukawa, et al. 2001. Interleukin-4 reversed the interleukin-1-inhibited proteoglycan synthesis through the inhibition of NO release: a possible involvement of intracellular calcium ion. Pathophysiology 7(4): 289–293.PubMedCrossRef
26.
go back to reference Hart, P.H., R.L. Cooper, and J.J. Finlay-Jones. 1991. IL-4 suppresses IL-1 beta, TNF-alpha and PGE2 production by human peritoneal macrophages. Immunology 72(3): 344–349.PubMed Hart, P.H., R.L. Cooper, and J.J. Finlay-Jones. 1991. IL-4 suppresses IL-1 beta, TNF-alpha and PGE2 production by human peritoneal macrophages. Immunology 72(3): 344–349.PubMed
Metadata
Title
Interleukin-4 Modulates the Inflammatory Response in Ifosfamide-Induced Hemorrhagic Cystitis
Authors
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
Publication date
01-02-2012
Publisher
Springer US
Published in
Inflammation / Issue 1/2012
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-011-9319-3

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