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Interleukin 1-beta, plasminogen activator system, and nerve growth factor in endometriosis associated deep dyspareunia

University of British Columbia

Endometriosis is defined as endometrial-like tissue present outside of the normal location (uterine lumen), and is an inflammatory disease that is a common cause of pelvic pain. The overwhelming effects of deep dyspareunia (pelvic pain during sexual intercourse) on patient quality-of-life are well known. Deep dyspareunia may be associated with locally invasive endometriosis (deep infiltrating endometriosis (DIE)) and/or local neurogenesis around endometriosis lesions. Interleukin 1β (IL-1β) and plasminogen activating system (PA) members (plasminogen activator inhibitor 1 (PAI-1) and urokinase plasminogen activator (uPA)), are known to play roles in tumorigenesis, cancer progression, and metastasis. IL-1β may be also involved in local neurogenesis through upregulation of nerve growth factor (NGF). I hypothesized that IL-1β and PA members play significant roles in endometriosis invasion, while IL-1β and NGF expression are associated with local neurogenesis, in the pathophysiology of endometriosis associated deep dyspareunia. Primary cultured endometriotic stromal cells were used for treatment, migration, and invasion assays. Immunohistochemical analysis on retrospectively and prospectively obtained surgically obtained endometriosis tissues was performed using validated antibodies for IL-1β, PAI-1 and uPA, NGF, as well as other antibodies, including for IL-1 active receptor (IL-1R1), the pan neuronal marker protein gene product 9.5 (PGP9.5), and substance P (SP). The immunohistochemistry data were correlated to comprehensive collection of clinical data from the corresponding endometriosis patients. My results showed that IL-1β enhances endometriotic stromal cells migration and invasion through up-regulating PA system members, and this effect was inhibited by IL-1R1 antagonist (Anakinra). Also, IL-1β, PAI-1, and uPA expression are higher in DIE, with IL-1β expression associated with severity of deep dyspareunia. In addition, IL-1β expression is correlated with NGF expression, local nerve fibre density, and severity of deep dyspareunia. Taken together, I have found evidence that endometriosis deep dyspareunia may be related, in part, to IL-1β associated invasion (DIE) via PA system members and to IL-1β associated neurogenesis via NGF. There is potential to block these pathways for novel treatment of endometriosis associated pain, such as via Anakinra as an inhibitor of IL-1 receptor.

Text

2024-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76343

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/