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Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis

Mbanefo, Evaristus C.; Le, Loc; Pennington, Luke F.; Odegaard, Justin I.; Jardetzky, Theodore S.; Alouffi, Abdulaziz; Falcone, Franco H.; Hsieh, Michael H.

Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis Thumbnail


Authors

Evaristus C. Mbanefo

Loc Le

Luke F. Pennington

Justin I. Odegaard

Theodore S. Jardetzky

Abdulaziz Alouffi

Franco H. Falcone

Michael H. Hsieh



Abstract

Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma hematobium homolog of IL-4-inducing principle from Schistosoma mansoni eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mastcells,triggering IL-4 secretion by thesecells. IPSE is also an “infiltrin,” translocating into the host nucleus to modulate gene transcription. Mice were administered IL-4, H-IPSE protein or its nuclear localization sequence (NLS) mutant, with or without neutralizing anti-IL-4 antibody, or 2-mercaptoethane sulfonate sodium (MESNA; a drug used to prevent IHC), followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency, and bladdergene expression analysis were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H-IPSE was superior to MESNA and IL-4 in suppressing bladder hemorrhage in an IL-4-dependent fashion and comparable with MESNA in dampening ifosfamide-triggered pain behaviors in an NLS-dependent manner. H-IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen-derived host modulatory molecule in a clinically relevant bladder disease model and indicates that IPSE may be an alternative to MESNA for mitigating CHC.

Citation

Mbanefo, E. C., Le, L., Pennington, L. F., Odegaard, J. I., Jardetzky, T. S., Alouffi, A., …Hsieh, M. H. (2018). Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis. FASEB Journal, 32(8), 4408-4419. https://doi.org/10.1096/fj.201701415r

Journal Article Type Article
Acceptance Date Feb 26, 2018
Online Publication Date Jul 30, 2018
Publication Date Aug 1, 2018
Deposit Date Aug 31, 2018
Publicly Available Date Mar 28, 2024
Journal The FASEB Journal
Print ISSN 0892-6638
Electronic ISSN 1530-6860
Publisher Federation of American Society of Experimental Biology (FASEB)
Peer Reviewed Peer Reviewed
Volume 32
Issue 8
Pages 4408-4419
DOI https://doi.org/10.1096/fj.201701415r
Keywords Biotechnology; Genetics; Biochemistry; Molecular Biology
Public URL https://nottingham-repository.worktribe.com/output/1055191
Publisher URL https://www.fasebj.org/doi/10.1096/fj.201701415R

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