{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:10:01Z","timestamp":1790651401031,"version":"4.1.0"},"reference-count":50,"publisher":"American Physiological Society","issue":"1","funder":[{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["U01DK082344"],"award-info":[{"award-number":["U01DK082344"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK111396"],"award-info":[{"award-number":["R01DK111396"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2019,7,1]]},"abstract":"<jats:p>Altered Toll-like receptor (TLR)4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis\/bladder pain syndrome (IC\/BPS). Our previously published human studies indicated that patients with IC\/BPS present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In the present study, we sought to determine whether altered TLR4 activation plays a role in pelvic\/bladder pain seen in patients with IC\/BPS using our validated IC\/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines IL-1\u03b2, IL-6, and TNF-\u03b1. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-\u03b1, glial activation markers CD11b and glial fibrillary acidic protein, and endogenous TLR4 ligand high mobility group box 1 was also observed after cystitis induction. Compared with URO-OVA mice, TLR4-deficient URO-OVA mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4-selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1\u03b2, IL-6, and TNF-\u03b1 as well as reduced spinal expression of mRNAs for IL-6, TNF-\u03b1, CD11b, glial fibrillary acidic protein, and high mobility group box 1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and therapeutic target for IC\/BPS pain.<\/jats:p>","DOI":"10.1152\/ajprenal.00017.2019","type":"journal-article","created":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T16:33:37Z","timestamp":1557938017000},"page":"F90-F98","source":"Crossref","is-referenced-by-count":28,"title":["Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study"],"prefix":"10.1152","volume":"317","author":[{"given":"Xiangrong","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Urology, University of Iowa, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Urology, 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