Target Inhibition of IL-1 Receptor Prevents Ifosfamide Induced Hemorrhagic Cystitis in Mice

Leite, Caio A.; Alencar, Viviane Teixeira Loiola de; Melo, Davi L.R.; Mota, José Maurício; Melo, Paulo H.; Mourão, Lívia Talita Cajaseiras; Wong, Deysi Viviana Tenazoa; Magalhães, Pedro J.C.; Santos, Armênio Aguiar dos; Brito, Gerly Anne Castro; Lima-Júnior, Roberto César Pereira; Cunha, Fernando; Ribeiro, Ronaldo A.

doi:10.1016/j.juro.2015.07.088

Cited by 19 publications

(17 citation statements)

References 29 publications

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“…Besides verifying that IPSE indeed could dampen ifosfamide-triggered hemorrhagic cystitis in an IL-4-dependent manner, we also found that many of IPSE's effects in this model relied upon an intact nuclear localization sequence [7,23]. In a subsequent RNA-Seq-based analysis, we confirmed that gene transcription related to TNF signaling is upregulated in ifosfamide-induced hemorrhagic cystitis [24], as reported by others using alternative experimental approaches [25,26]. Moreover, through this analysis we discovered that IPSE reduces expression of ifosfamide-induced genes related to the TNF pathway.…”

Section: Discussionsupporting

confidence: 87%

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

Ishida

Mbanefo²,

et al. 2020

Preprint

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The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4-and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE's analgesic effect. In contrast, IPSE's analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin-and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE's nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1expressing neurons and/or may rely upon urothelial mechanisms.

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Section: Discussionsupporting

confidence: 87%

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

Ishida

Mbanefo²,

et al. 2020

Preprint

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“…Most probably, IL‐1β and IL‐6 are particularly involved in the toxic effects reported after CYP administration. It was shown that an IL‐1 receptor blocker (ie, anakinra) reduced hemorrhage and inflammatory response after CYP‐treatment in rodents as well as improved the functional bladder parameters . Moreover, via induction if the inducible iNOS, IL‐1β (and TNF‐α) mediates generation of NO .…”

Section: Discussionmentioning

confidence: 99%

“…It was shown that an IL-1 receptor blocker (ie, anakinra) reduced hemorrhage and inflammatory response after CYP-treatment in rodents as well as improved the functional bladder parameters. 22 Moreover, via induction if the inducible iNOS, IL-1β (and TNF-α) mediates generation of NO. 2 It was shown that inhibition of TNF-α and IL-1β diminished the urothelial erosion, hemorrhage, edema, and leukocyte migration.…”

Section: Discussionmentioning

confidence: 99%

Intravesical administration of blebbistatin prevents cyclophosphamide‐induced toxicity of the urinary bladder in female Wistar rats

Wróbel

Serefko

Bańczerowska‐Górska

et al. 2019

Neurourology and Urodynamics

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Aims The main goal of our study was to investigate whether blebbistatin would prevent the cyclophosphamide (CYP)‐induced changes in cystometric and inflammatory parameters indicating the development of bladder inflammation and bladder overactivity. As the nature of CYP‐induced urotoxicity is inflammatory, we assume that agents presenting an anti‐inflammatory potential, such as blebbistatin, are worth special attention. Materials and Methods The experiments were carried out in female Wistar rats. Surgical procedures, cystometric investigations, measurements of bladder edema and urothelium thickness as well as biochemical analyses were performed according to the published literature. Results As expected, an acute administration of CYP (200 mg/kg, intraperitoneally) induced changes in the cystometric parameters and the levels of the tested biomarkers (ie, interleukin 1‐β, interleukin 6, interleukin 10, tumor necrosis factor‐α, nerve growth factor, brain‐derived neurotrophic factor, heparin‐binding epidermal growth factor‐like growth factor, insulin‐like growth factor‐binding protein 3, C‐X‐C motif chemokine 10, orosomucoid‐1, Tamm‐Horsfall protein, hemopexin, and occludin), indicating the development of bladder overactivity and bladder inflammation, respectively. These changes were accompanied by bladder edema and increased urothelium thickness. Intravesical infusion of blebbistatin for 7 days (125 nmol/day) prevented all symptoms of the CYP‐induced urotoxicity. Conclusions Blebbistatin might be a promising novel agent for the treatment of bladder dysfunctions, like CYP‐induced hemorrhage cystitis or bladder overactivity, since it diminished the increased urinary bladder levels of proinflammatory markers and normalized the concentrations of the anti‐inflammatory ones. This effect was accompanied by amelioration of bladder edema and permeability, and normalization of both urothelium thickness and values of the cystometric parameters.

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“…The transition of the bladder mucosa from a homeostatic innate immune response to acute disease reflects the molecular control of IL-1β processing, through inflammasome-dependent or non-canonical mechanisms ( Fig 8 ), [ 44 – 46 ]. The findings suggest that acute cystitis might resemble hyper-inflammatory disorders [ 28 , 47 , 48 ], where therapeutic efficacy of IL-1β inhibitors has been documented [ 49 , 50 ]. The results provide a molecular context for acute cystitis and for the susceptibility to acute cystitis in patients with severe and chronic disease.…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets

et al. 2016

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Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc -/- and Nlrp3 -/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc -/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man.Trial RegistrationThe clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www.clinicaltrials.gov).

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Target Inhibition of IL-1 Receptor Prevents Ifosfamide Induced Hemorrhagic Cystitis in Mice

Abstract: Anakinra is effective for preventing experimentally ifosfamide induced hemorrhagic cystitis. It seems that neutrophil and macrophage infiltration in this circumstance depends on IL-1 signaling through IL1R. Possibly TNFR2 has a protective role in hemorrhagic cystitis.

Cited by 19 publications

References 29 publications

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

Intravesical administration of blebbistatin prevents cyclophosphamide‐induced toxicity of the urinary bladder in female Wistar rats

Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets

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