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Interleukin-6 (IL-6) is a major driver of acute phase inflammatory response during chemotherapy induced hemorrhagic cystitis
Evaristus Mbanefo, PhD1, Loc Le, PhD1, Kenji Ishida, PhD1, Rebecca Zee, MD,PhD2, Nirad Banskota, MS1, Luke Pennington, MD,PhD3, Abdulaziz Alouffi, PhD4, Theodore Jardetzky, MD,PhD3, Franco Falcone, PhD4, Michael Hsieh, MD/PhD5.
1Biomedical Research Institute, Rockville, MD, USA, 2Children's National Medical Center, Washington DC, DC, USA, 3Stanford University School of Medicine, Stanford, CA, USA, 4University of Nottingham, Nottingham, United Kingdom, 5Children National Medical Center, Washington, DC, USA.

BACKGROUND: Cancer therapy using the cyclophosphamide drugs family can result in hemorrhagic cystitis, a debilitating severe adverse effect which can be difficult to manage. Especially for the pediatrics population, the available options for preventing or treating this condition are either suboptimal in efficacy or present significant untoward effects themselves, some of which are irreversible. Although it is known that cyclophosphamide-induced hemorrhagic cystitis is due to the accumulation of a toxic byproduct called acrolein in the bladder, the exact mechanism underlying this acute severe toxic effect is not fully understood. To provide new insights, we undertook transcriptional profiling of bladder tissues from cyclophosphamide treated mice.
METHODS: Mice were injected intraperitoneally with either 400 mg/kg body weight of ifosfamide in saline, or give the saline vehicle. Bladder RNA was purified 12 hours later and subjected to RNA-seq. We adopted the RNA-seq analysis pipeline comprising tools available in Galaxy, and pathway analysis on the Ingenuity Pathways Analysis (IPA) platform.
RESULTS: There was overt upregulation of a wide range of pro-inflammatory genes. IL-6 was one of the top upregulated genes driving acute phase inflammation, in addition to TNF-a, PTX3 (a TNF-inducible gene) and EID3 (an inhibitor of cancer suppression). Also upregulated were HMOX1 (a key enzyme in the heme homeostasis pathway), leucocyte extravasation related genes and several chemokines. TNF-a, beta-estradiol, NFkB, IL-1b and other inflammatory genes were identified as the top activated upstream regulators, in contrast to TGF-b and the cancer suppressor TP53, which were the top inhibited regulators. These genes are involved in downstream pathways, including the NFkB, HMGB1 and the STAT3 pathways drive the acute phase inflammation and release of pro-inflammatory mediators, characteristic of chemotherapy induced hemorrhagic cystitis. FZD10 (Frizzled class receptor 10) of the Wnt receptor signaling pathway was among the top downregulated genes, in addition to the cytochrome p450 gene, which suggests a negative feedback mechanism against cyclophosphamide metabolism.
CONCLUSIONS: We identified signatures of acute phase inflammatory response, leucocyte infiltration in addition to heme homeostatic activity as expected during severe hemorrhage. There were also key features of cell proliferation, necrosis, oxidative stress and carcinogenesis. This study has revealed several pathways that can be targeted for development of novel therapies to prevent chemotherapy-induced hemorrhagic cystitis. To our knowledge, this is the first description of the transcriptomic changes associated with the use of cyclophosphamide drugs.

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