PT  - JOURNAL ARTICLE
AU  - Evaristus C. Mbanefo
AU  - Loc Le
AU  - Rebecca Zee
AU  - Nirad Banskota
AU  - Kenji Ishida
AU  - Luke F. Pennington
AU  - Justin I. Odegaard
AU  - Theodore S. Jardetzky
AU  - Abdulaziz Alouffi
AU  - Franco H. Falcone
AU  - Michael H. Hsieh
TI  - IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways
AID  - 10.1101/381764
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 381764
4099  - http://biorxiv.org/content/early/2018/08/03/381764.short
4100  - http://biorxiv.org/content/early/2018/08/03/381764.full
AB  - 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, a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the exact mechanisms underlying this urotoxic effect 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 IPSE pretreatment. Following ifosfamide challenge, there was upregulation of a range of pro-inflammatory genes. The pro-inflammatory pathway involving the IL-1β, TNFα and IL-6 triad via NFκB and STAT3 signaling pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates both Hmox1-mediated heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory and cellular proliferation cascades implicated in tissue repair, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE administration before ifosfamide injection resulted in significant downregulation of major proinflammatory pathways including the triad of IL-1β, TNFα and IL-6 pathways, the interferon signaling pathway, and less apparent reduction in oxidative stress responses. Taken together, we have identified signatures of acute phase inflammation and oxidative stress responses in the ifosfamide-injured bladder, which are reversed by pretreatment with IPSE, a parasite derived anti-inflammatory molecule. In addition to providing new insights into the underlying mechanism of IPSE’s therapeutic effects, this work has revealed several pathways that could be therapeutically targeted to prevent and treat ifosfamide-induced hemorrhagic cystitis.AbbreviationsIPSEinterleukin-4 inducing principle from Schistosoma eggsMESNA2-mercaptoethane sulfonate Sodium