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Sci Rep. 2019 Feb 7;9(1):1586. doi: 10.1038/s41598-018-38274-z.

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

Author information

1
Bladder Immunology Group, Biomedical Research Institute, Rockville, MD, USA.
2
Division of Urology, Children's National Medical Center, Washington, DC, USA.
3
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
4
Guardant Health, Redwood City, CA, USA.
5
Life Science & Environment Sector, King Abdulaziz City for Science & Technology (KACST), Riyadh, Saudi Arabia.
6
Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK.
7
Bladder Immunology Group, Biomedical Research Institute, Rockville, MD, USA. mhsieh@afbr-bri.org.
8
Division of Urology, Children's National Medical Center, Washington, DC, USA. mhsieh@afbr-bri.org.
9
Department of Urology, The George Washington University, Washington, DC, USA. mhsieh@afbr-bri.org.

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.

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