Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis
Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma haematobium homolog of Interleukin-4...
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| Format: | Article |
| Language: | English |
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Federation of American Society of Experimental Biology
2018
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| Online Access: | https://eprints.nottingham.ac.uk/50318/ |
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| author | Mbanefo, Evaristus C. Le, Loc Pennington, Luke F. Odegaard, Justin I. Jardetzky, Theodore S. Alouffi, Abdulaziz Falcone, Franco H. Hsieh, Michael H. |
| author_facet | Mbanefo, Evaristus C. Le, Loc Pennington, Luke F. Odegaard, Justin I. Jardetzky, Theodore S. Alouffi, Abdulaziz Falcone, Franco H. Hsieh, Michael H. |
| author_sort | Mbanefo, Evaristus C. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma haematobium homolog of Interleukin-4-inducing principle from Schistosoma mansoni Eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. 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 MESNA, followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency and gene expression 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-and NLS-dependent fashion, and comparable to 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. |
| first_indexed | 2025-11-14T20:16:17Z |
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| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:16:17Z |
| publishDate | 2018 |
| publisher | Federation of American Society of Experimental Biology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-503182018-09-27T10:23:58Z https://eprints.nottingham.ac.uk/50318/ 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. Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma haematobium homolog of Interleukin-4-inducing principle from Schistosoma mansoni Eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. 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 MESNA, followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency and gene expression 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-and NLS-dependent fashion, and comparable to 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. Federation of American Society of Experimental Biology 2018 Article PeerReviewed application/pdf en cc_by https://eprints.nottingham.ac.uk/50318/1/fj.201701415r.pdf Mbanefo, Evaristus C., Le, Loc, Pennington, Luke F., Odegaard, Justin I., Jardetzky, Theodore S., Alouffi, Abdulaziz, Falcone, Franco H. and Hsieh, Michael H. (2018) Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis. FASEB Journal, 32 (8). pp. 4408-4419. ISSN 1530-6860 Infiltrin; Anti-inflammation; Ifosfamide; Allodynia; Urothelial repair https://www.fasebj.org/doi/10.1096/fj.201701415R doi:10.1096/fj.201701415R doi:10.1096/fj.201701415R |
| spellingShingle | Infiltrin; Anti-inflammation; Ifosfamide; Allodynia; Urothelial repair 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 |
| title | Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis |
| title_full | Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis |
| title_fullStr | Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis |
| title_full_unstemmed | Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis |
| title_short | Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis |
| title_sort | therapeutic exploitation of ipse, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis |
| topic | Infiltrin; Anti-inflammation; Ifosfamide; Allodynia; Urothelial repair |
| url | https://eprints.nottingham.ac.uk/50318/ https://eprints.nottingham.ac.uk/50318/ https://eprints.nottingham.ac.uk/50318/ |