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Substance P receptor-dependent genes and TFs

ABSTRACT: Tachykinins (TKs) are a family of peptides involved in the peripheral and central regulation of urinary functions through the stimulation of neurokinin (NK) NK1, NK2 and NK3 receptors. Recent evidence indicates that NK1 receptors are required in antigen-induced cystitis. Therefore, determining the regulatory network downstream NK1 receptor activation is a key step toward understanding the role of TKs in inflammation. For this purpose, we used a Transcriptional Regulatory Network Analysis (TRNA) to identify biologically relevant transcriptional regulatory elements (TRE) that underline the NK1-dependent gene expression in bladder responses to inflammation. Gene expression analysis was obtained using the urinary bladder isolated from WT and NK1-R-/- mice that were stimulated with intravesical instillation of saline or antigen challenge (in sensitized mice) in order to promote cystitis. Based on cDNA array results, we selected a cluster of genes that was dependent on NK1 receptors for their up-regulation in response to inflammation. Next, we used PAINT database to retrieve upstream promoter sequences for those NK1-R-dependent genes and to identify TREs on those promoters. Finally, TREs were enriched statistically by selecting only those that were significantly expressed and a regulatory network downstream of NK1 receptor activation was determined. This work indicates an overriding participation of NK1 receptors in bladder inflammation, provides a working model for the involvement of transcription regulators such as AP1, NF-kB, and Nkx-2.5, and evokes testable hypotheses regarding the regulatory network downstream of NK1 receptor activation. Keywords: URINARY BLADDER INFLAMMATION

ORGANISM(S): Mus musculus

PROVIDER: GSE2821 | GEO | 2005/06/17

SECONDARY ACCESSION(S): PRJNA92377

REPOSITORIES: GEO

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Project description:Acute cystitis is rapidly becoming a therapeutic enigma, as antibiotic resistance is reducing the options to a minimum. Fortunately, new insights are now making it possible to explore immune response modifiers as alternatives to antibiotics. In patients with acute cystitis, infection triggers a rapid and potent inflammatory response in the bladder mucosa and clinical symptoms include pain, urgency and frequency of urination. The molecular basis of these symptoms is not well understood, but bacterial interactions with the bladder epithelium have been shown to create inflammatory cascades. This study examined how innate immune response genes influence the outcome of bladder infection and the pathogenesis of acute cystitis with a particular focus on IL-1β. C57BL/6 mice were intravesically infected with relevant uropathogenic Escherichia coli strain, CFT073. Acute cystitis in infected bladders was defined by macroscopic inspection of edema, hyperemia and purulent discharge followed by histology and immunohistochemistry, after 24 hours and seven days. Genetic determinants of transient bladder inflammation versus severe disease were subsequently identified using C57BL/6 mice with specific inflammasome gene deletions (Il1b-/-, Casp1-/-, Asc-/- and Nlrp3-/-). Using genome-wide transcriptomic analysis to characterize genes regulated by infection in the bladders of these mice, we identified acute cystitis as an IL-1β-driven, hyper-inflammatory disease. Consistent with such a role, Il1b-/- mice were protected from infection and pathology. In contrast Asc-/- and Nlrp3-/- mice developed progressive IL-1β-driven bladder inflammation and severe pathology, caused by a new, non-canonical IL-1β processing mechanism, involving the metalloproteinase MMP-7. Using IL-1β and MMP-7 as targets for immunotherapy, we succeeded in protecting susceptible Asc-/- mice against acute cystitis, confirming the potential of immunotherapy for this indication. The results reproduce important aspects of human cystitis in the murine urinary tract infection (UTI) model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common bacterial infections in man.

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Substance P receptor-dependent genes and TFs

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