IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors

Abstract

Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neo-angiogenesis or establishment of new blood supply is one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and pro-inflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells and human umbilical vein endothelial cells with IL-17A revealed significant increase in angiogenic (VEGF, IL-8), pro-inflammatory (IL-6, IL-1β) and chemotactic cytokines (G-CSF, CXCL12, CXCL1, CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on matrigel in a dose-dependent manner. Thus we provide the first evidence that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data shows a likely important role of IL-17A in promoting angiogenesis and pro-inflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.

Endometriosis-associated changes in serum levels of interferons and chemokines

“…Regarding IL-17A, a very recent study showed differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Moreover, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations, thus showing that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to a significant reduction in systemic levels of IL-17A (28). Our results show similar levels between endometriosis patients and controls, thus adding to the controversy around the role of IL-17A in the context of endometriosis.…”

Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients

“…Endometrial cells have been shown to produce IL-8 and to have increased expression of IL-8 and cyclooxygenase (COX) 2 under stimulation of IL-17 in vitro (28), meaning they can stimulate local blood vessel formation. Our group recently confirmed that IL-17A is expressed in the eutopic and ectopic endometrium of women with endometriosis, and that IL-17A stimulation of cultured endometrial cells induces the production of VEGF, G-CSF, PDGF-AA, and stromal cell–derived factor 1 (23), which could be a mechanism by which ectopic lesions increase IL-8 production.…”

“…Additionally, ectopic tissue was found to express higher levels of GM-CSF than eutopic tissue, further indicating that ectopic lesions are driving the aberrant expression of this cytokine. Meanwhile, IL-8 is a chemotactic and angiogenic factor previously shown to contribute to neutrophil recruitment and blood vessel formation in endometriotic lesions (23, 24). High levels of IL-8 have previously been detected in the PF and serum of women with endometriosis (25, 26), which supports our findings.…”

Extracellular vesicle mediated intercellular communication at the porcine maternal-fetal interface: A new paradigm for conceptus-endometrial cross-talk

“…Cell proliferation assay was performed as previously described52. Briefly, PAOEC and PTr2 cells were cultured at the rate of 1.25 × 10 4 cells/well in two separate 96 well plates for 24 hrs.…”