Abstract
Pelvic pain in women with endometriosis is attributed to neuroinflammation and afferent nociceptor nerves in ectopic and eutopic endometrium. The hypothesis that uterine nociception is activated by IL-1β, a prominent cytokine in endometriosis, was tested herein. Immunofluorescence histochemistry confirmed the presence of neurons in human endometrial tissue. Expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and their receptors in endometrial tissue and cells was validated by immunohistochemistry and Western blotting. Isolated endometrial stromal cells (ESCs) were subjected to dose-response and time-course experiments with IL-1β and kinase inhibitors to characterize in vitro biomarkers. Neural biomarkers were co-localized in endometrial nerve fibers. NGF, BDNF, and their receptors tropomyosin receptor kinase (Trk) A, TrkB, and p75 neurotrophin receptor were all expressed in primary ESCs. IL-1β stimulated higher TrkA/B expression in ESCs derived from endometriosis cases (2.8- ± 0.2-fold) than cells from controls (1.5- ± 0.3-fold, t-test, P < 0.01), effects that were mediated via the c-Jun N-terminal kinase (JNK) pathway. BDNF concentrations trended higher in peritoneal fluid of endometriosis cases but were not statistically different from controls (P = 0.16). The results support the hypothesis that NGF and BDNF and their corresponding receptors orchestrate innervation of the endometrium, which is augmented by IL-1β. We postulate that JNK inhibitors, such as SP600125, have the potential to reduce neuroinflammation in women with endometriosis.