An increased level of IL-6 suppresses NK cell activity in peritoneal fluid of patients with endometriosis via regulation of SHP-2 expression

• Published in: Human reproduction (Oxford) Vol. 29; no. 10; pp. 2176 - 2189
• Main Authors: Kang, Young-Ju, Jeung, In Cheul, Park, Arum, Park, Young-Jun, Jung, Haiyoung, Kim, Tae-Don, Lee, Hee Gu, Choi, Inpyo, Yoon, Suk Ran
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 10.10.2014
• Subjects: Adult; Ascitic Fluid - cytology; Ascitic Fluid - immunology; Ascitic Fluid - metabolism; Cell Differentiation; Endometriosis - immunology; Endometriosis - metabolism; Endometriosis - pathology; Female; Gene Expression Regulation; Humans; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Interleukin-6 - physiology; Killer Cells, Natural - physiology; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; endometriosis; SHP-2; natural killer cell; IL-6; cytotoxicity
• DOI: 10.1093/humrep/deu172
• ISSN: 0268-1161

STUDY QUESTION Is the decreased natural killer (NK) cell cytolytic activity in the peritoneal fluid (PF) of endometriosis patients due to primary cytokine activity? SUMMARY ANSWER An increased level of interleukin-6 (IL-6) in the PF of patients with endometriosis suppresses NK cell cytolytic activity by down-regulating cytolytic granule components, such as granzyme B and perforin, through the modulation of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) expression. WHAT IS ALREADY KNOWN Endometriosis is known to be related to a defect in NK cell cytolytic activity. Additionally, the levels of inflammatory cytokines are elevated in the PF of women with endometriosis. STUDY DESIGN, SIZE, DURATION The effects of PF on the differentiation and functional activity of NK cells were investigated in patients with or without endometriosis, and cytokines that reduce NK cell cytolytic activity in endometriosis patients were examined. The study included women who underwent laparoscopic examination for the diagnosis of endometriosis from August 2012 to July 2013 (33 women with, and 15 women without, endometriosis). PARTICIPANTS/MATERIALS, SETTING, METHODS Women of reproductive age (20–40 years old) who underwent laparoscopic examination for endometriosis were included. Cytokines present in the PF were identified by enzyme-linked immunosorbent assay. The cytolytic activity of NK cells in the PF was also analyzed using a calcein-acetoxy methyl ester (AM) release assay. MAIN RESULTS AND THE ROLE OF CHANCE PF from patients with endometriosis suppressed the differentiation and cytotoxicity of NK cells compared with PF from controls (P < 0.05). Increased levels of IL-6 were also found in the PF of patients with endometriosis (P < 0.01), and IL-6 levels were negatively correlated with the cytolytic activity of NK cells (rs = −0.558, P = 0.03). Furthermore, IL-6 reduced the cytolytic activity of NK cells, concomitantly with the down-regulation of granzyme B and perforin (P < 0.05), by modulating SHP-2. Importantly, the addition of anti-IL-6 to the PF of endometriosis patients restored the activity of NK cells (P < 0.01), suggesting that IL-6 plays a crucial role in the reduction of NK cell activity in the PF of patients with endometriosis. LIMITATIONS, REASONS FOR CAUTION PF contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the differentiation and activity of NK cells. WIDER IMPLICATIONS OF THE FINDINGS Our results imply that the suppression of IL-6 using an anti-IL-6 antibody or soluble IL-6 receptor could rescue the impairment of NK cell activity in patients with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the KRIBB Creative Research Program (KCS3051312); the STP project (DTM0111221) of the Ministry of Knowledge & Economy and the Basic Science Research Program (RBM0271312) of the National Research Foundation of Korea (NRF) from the Ministry of Education, Science & Technology. There are no conflicts of interest.