IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways
| Autor: | Loc Le, Theodore S. Jardetzky, Luke F. Pennington, Rebecca Zee, Michael H. Hsieh, Franco H. Falcone, Justin I. Odegaard, Nirad Banskota, Evaristus Chibunna Mbanefo, Kenji Ishida, Abdulaziz Alouffi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Medicine Peroxisome proliferator-activated receptor Inflammation Hemorrhage medicine.disease_cause Article Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cystitis Medicine Ifosfamide lcsh:Science STAT3 Antineoplastic Agents Alkylating 030304 developmental biology chemistry.chemical_classification 0303 health sciences Multidisciplinary biology business.industry Gene Expression Profiling lcsh:R Egg Proteins Wnt signaling pathway Helminth Proteins medicine.disease 3. Good health Oxidative Stress 030104 developmental biology chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Cytokines lcsh:Q Signal transduction medicine.symptom Inflammation Mediators business Transcriptome 030217 neurology & neurosurgery Oxidative stress medicine.drug Hemorrhagic cystitis Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019) |
| ISSN: | 2045-2322 |
| Popis: | 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, TNFαand 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 bothHmox1-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, TNFαand 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. |
| Databáze: | OpenAIRE |
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