IL-1β stimulates the upregulation of neurotrophins and their receptors in endometrial stromal cells through the JNK signaling pathway. (2023)

Undergraduate: Eric Zou

Faculty Advisor: Robert Taylor
Department: OB-GYN

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Pelvic pain manifested in women with endometriosis is attributed to afferent nociceptors and neuroinflammation in their ectopic and eutopic endometrium. The study aimed to investigate the potential role of IL-1β, a prominent cytokine in endometriosis, in activating nociceptive endometrial nerves, and how this activation may influence the expression of endometrial neutrophils and their receptors in vitro. Immunofluorescence histochemistry was used to confirm the presence of neurons in human endometrial tissue. Expression of NGF and BDNF and their receptors in endometrial tissue and cells were validated by immunohistochemistry and Western blotting. Isolated endometrial stromal cells (ESC) were subjected to dose-response and time-course experiments in the absence or presence of IL-1β as an inflammatory stimulus. Specific kinase inhibitors were used to characterize the predominant pathways. NGF, BDNF, and their receptors TrkA, TrkB, and p75 NTR were all expressed in primary ESC. IL-1β stimulated higher TrkA/B expression in ESC derived from endometriosis cases (2.8 ± 0.2-fold) than cells from control subjects (1.5 ± 0.3-fold, t-test, P<0.01). These effects were mediated via an intracellular c-Jun N-terminal Kinase (JNK) cascade. BDNF concentrations trended higher in peritoneal fluid of endometriosis cases but were not statistically different from controls (P=0.16). Our results support the hypothesis that NGF and BDNF and their receptors orchestrate innervation of the endometrium, which is augmented by IL-1β. We postulate that JNK inhibitors, like SP600125, could be developed as therapeutic agents to reduce neuroinflammation in women with endometriosis-associated pain

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