Figure 4

The IL-1β, TNFα, and IL-6 pathways, a major inflammatory pathway upregulated in the bladder during ifosfamide-induced hemorrhagic cystitis was downregulated by IPSE pretreatment. (A) Pathway and functional analyses were generated through the use of IPA⁵⁷. Bladders of ifosfamide-exposed mice upregulated expression of genes from the IL-1β, TNFα and IL-6 pathways and their corresponding receptors and downstream nuclear transcriptional factors. In the case of IL-1β and TNFα, these cascades converge upon NFκB. IL-6 also indirectly interacts with NF𝜅B through ERK1/2 activation of NF-IL6, which works with NFκB to promote transcription of target genes. Keys: upregulation (red), downregulation (green), cytokines (square), growth factors (dotted square), phosphatase (triangle), kinases (inverted triangle), transmembrane receptors (ellipse), transcriptional regulators (wide circle), peptidase (rhombus), group or complex (double lined shapes), transporter (trapezium), acts on (line with filled arrow), translocate (line with open arrow), inhibition (line with perpendicular line at edge). (B) Il1b, Tnfa, Il6 and Ptx3 gene transcription were upregulated by 2–3 orders of magnitude in the bladders of ifosfamide-treated mice. Pretreatment with IPSE or its NLS mutant reduced the levels by ~50% relative to the ifosfamide-treated group. Similar trends were observed for cognate receptors and downstream transcription factors (data not shown).