IL-1 beta Stimulates Brain-Derived Neurotrophic Factor Production in Eutopic Endometriosis Stromal Cell Cultures A Model for Cytokine Regulation of Neuroangiogenesis

Endometriosis implants are comprised of glandular and stromal elements, macrophages, nerves, and blood vessels and are commonly accompanied by pelvic pain. We propose that activated macrophages are recruited to and infiltrate nascent lesions, where they secrete proinflammatory cytokines, promoting the production of chemokines, neurotrophins, and angiogenic growth factors that sustain an inflammatory microenvironment. Immunohistochemical evaluation of endometriosis lesions reveals in situ colocalization of concentrated macrophages, brain-derived neurotrophic factor (BDNF), and nerve fibers. These observations were coupled with biochemical analyses of primary eutopic endometriosis stromal cell (EESC) cultures, which allowed defining potential pathways leading to the neuroangiogenic phenotype of these lesions. Our findings indicate that IL-1 beta potently (EC50 = 7 +/- 2 ng/mL) stimulates production of EESC BDNF at the mRNA and protein levels in an IL-1 receptor-dependent fashion. Selective kinase inhibitors demonstrate that this IL-1 beta effect is mediated by c-Jun N-terminal kinase (JNK), NE-kappa B, and mechanistic target of rapamycin signal transduction pathways. IL-1 beta regulation of regulated on activation normal T cell expressed and secreted (RANTES), a prominent EESC chemokine, also relies on JNK and NE-kappa B. An important clinical implication of the study is that interference with BDNF and RANTES production, by selectively targeting the JNK and NE-kappa B cascades, may offer a tractable therapeutic strategy to mitigate the pain and inflammation associated with endometriosis.