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IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways

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

Authors

Evaristus C. Mbanefo

Loc Le

Rebecca Zee

Nirad Banskota

Kenji Ishida

Luke F. Pennington

Justin I. Odegaard

Theodore S. Jardetzky

Abdulaziz Alouffi

Franco H. Falcone

Michael H. Hsieh



Abstract

Ifosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE (Interleukin-4-inducing principle from Schistosoma eggs), a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the mechanisms underlying this urotoxicity and its prevention are not fully understood. To provide insights into IPSE’s protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without pretreatment with IPSE or IPSE-NLS (a mutant of IPSE lacking nuclear localization sequence). Ifosfamide treatment upregulated a range of proinflammatory genes. The IL-1β-TNFα-IL-6 proinflammatory cascade via NFκB and STAT3 pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory cascades, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE drove significant downregulation of major proinflammatory pathways including the IL-1β-TNFα-IL-6 pathways, interferon signaling, and reduction in oxidative stress. IPSE-NLS reduced inflammation but not oxidative stress. Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE. This work revealed several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis.

Journal Article Type Article
Publication Date Feb 7, 2019
Journal Scientific Reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 9
Article Number 1586
APA6 Citation Mbanefo, E. C., Le, L., Zee, R., Banskota, N., Ishida, K., Pennington, L. F., …Hsieh, M. H. (2019). IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways. Scientific Reports, 9, https://doi.org/10.1038/s41598-018-38274-z
DOI https://doi.org/10.1038/s41598-018-38274-z
Publisher URL https://www.nature.com/articles/s41598-018-38274-z
Additional Information Received: 28 September 2018; Accepted: 18 December 2018; First Online: 7 February 2019; : The authors declare no competing interests.

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