자궁내막증 환자의 복강 액내 IL-6와 TNF-α의 변화 양상에 관한 연구

A Study of Altered IL-6 and TNF-α Expression in Peritoneal Fluid of Patients with Endometriosis

  • 강정배 (한림대학교 의과대학 산부인과학교실) ;
  • 이영경 (한림대학교 의과대학 진단검사의학과학교실)
  • Kang, Jeong-Bae (Department of Obstetrics and Gynecology, Hallym University, College of Medicine) ;
  • Lee, Young-Kyeong (Department of Laboratory Medicine, Hallym University, College of Medicine)
  • 발행 : 2006.03.31

초록

목 적: 자궁내막증과 이로 인한 불임의 원인인 면역학적 인자 중 세포-매개성 면역계의 변화 양상을 규명하기 위하여 자궁내막증 환자와 자궁내막중이 없는 환자의 복강 액을 채취하여 면역 세포의 분포양상을 비교 분석하고자 IL-6와 TNF-${\alpha}$를 측정하였다. 연구방법: 자궁내막증으로 육안적 또는 조직검사로 확진된 환자 또는 불임검사를 위해 진단적 복강경을 시행한 34명을 연구군으로 등록하였으며 본 연구 이전에 자궁내막증과 관련된 어떠한 치료도 받은 적이 없거나 복강경 시술이나 개복수술과정에서 자궁내막증 소견과 증상이 없는 환자 37명을 대조군으로 하였다. 두 군의 복강 액을 추출한 다음 30분 이내에 $400g{\times}10$분 동안 원심분리 후 상층액만 검사용기에 모아 밀봉한 후 $-70^{\circ}C$ 냉동실에 보관하여 IL-6와 TNF-${\alpha}$의 농도를 "sandwich" enzyme-linked immunosorbent assays (ELISA: R & D Systems, Minnepolis, MN)로 측정하였다. 결 과: 1. 복강 액의 IL-6의 농도는 자궁내막증으로 확진된 연구군에서는 $38.9{\pm}19.7pg/ml$으로 대조군의 $22.4{\pm}10.2pg/ml$보다 유의하게 증가하였고 (p=0.02), TNF-${\alpha}$의 농도도 자궁내막증이 있는 여성에서 $20.6{\pm}8.6pg/ml$로 대조군의 $6.2{\pm}3.5pg/ml$보다 유의하게 증가하였다 (p=0.01). 2. 자궁내막증여성의 생리주기별 농도에서 IL-6은 증식기보다 분비기에 유의하게 증가한 반면 (p=0.01), TNF-${\alpha}$는 차이가 없었다 (p>0.05). 3. IL-6은 가임여성보다 불임여성에서 유의하게 증가하였고 (p=0.03), TNF-${\alpha}$는 두 군 간에 유의한 차이는 없었다 (p>0.05). 4. IL-6과 TNF-${\alpha}$ 모두 대조군과 자궁내막증 병기 I과 II는 통계학적인 유의성은 없었으나 병기 III과 IV는 유의하게 증가하였다 (p<0.05). 결 론: 자궁내막증인 환자의 복강 액에서 IL-6와 TNF-${\alpha}$가 증가하여 자궁내막증의 생성과 유지, 증상발현에 관여하며 불임의 유발 요인으로 여겨지나 향후 많은 환자를 대상으로 한 연구와 자궁내막증과 각종 cytokine과의 상호 연관관계에 대한 연구가 더 많이 필요하리라 사료된다.

Objective: Our purpose was to investigate the relationship between the levels of IL-6 and tumor necrosis factor-${\alpha}$ in the peritoneal fluid of women with and without endometriosis and infertile women. Methods: This study is prospective and case-control study in University hospital, enrolled thirty-four women with laparoscopic findings of minimal to severe endometriosis, and thirty-seven women with no visual evidence of pelvic endometriosis and with benign gynecologic disease. IL-6 and tumor necrosis factor-${\alpha}$ levels in peritoneal fluid were determined using commercial ELISA. IL-6 and tumor necrosis factor-${\alpha}$ concentrations were compared among women with and without endometriosis, and with infertile and fertile women, and then also compared according the revised American Fertility Society classification. Results: IL-6 and tumor necrosis factor-${\alpha}$ concentrations were higher than in the peritoneal fluid of women with endometriosis than in matched normal controls. Cyclic variations in IL-6 concentrations were seen in peritoneal fluid from patients with endometriosis: the concentrations in the secretory phase were significantly higher than those in the proliferative phase. The concentrations were higher than among of infertile women than in fertile women. A significant correlation between IL-6 and tumor necrosis factor-${\alpha}$ concentrations and endometriosis stage III and IV was noted. Conclusion: Increased levels of IL-6 and tumor necrosis factor-${\alpha}$ in patients with endometriosis in the peritoneal fluid may be relate to the pathogenesis of endometriosis suggesting that partially contribute to the disturbed immune regulation observed in patients with endometriosis.

키워드

참고문헌

  1. Katayama KP, Ju KS, Manual M, Koyama N, Matsuura K, Okamura H. Computer analysis of etiology and pregnancy rate in 636 cases of primary infertility. Am J Obstet Gynecol 1979; 135: 207-9
  2. Malinak LR, Buttram VC, Elias S. Heritable aspects of endometriosis: Clinical characteristics of familial endometriosis. Am J Obster Gynecol 1980; 137: 332-9
  3. Jonathan SB, Eli YA, Paula AH. Novak's textbook of gynecology. 13th ed. Lippincott Willliams and Wilkins 2002; 933-4
  4. Muse K, Wilson EA, Jawad MJ. Prolactin hyperstimulation in response to thyrotropin-releasing hormone in patients with endometriosis. Fertil Steril 1982; 38: 419-25
  5. Jonhes SE, Parsons AK, Becker JL. Altered interleukin-6 production by peritoneal leukocytes from patients with endometriosis. Fertil Steril 1988; 61: 294-9
  6. Juha Punnonen, Klaus Teisala, Hannu Ranta, Bruce Bennett, Reijo Punnonen. Increased levels of interleukin-6 and interleukin-1O in the peritoneal fluid of patients with endometriosis. Am J Obstet Gynecol 1996; 174: 1510-22
  7. Iwabe T, Harada T, Sakamoto Y. Gomadotropin-releasing hormone agonist treatment reduced serum interleukin-6 concentrations in patients with ovarian endometriosis. Fertil Steril 2003; 80: 300-4
  8. Kishimoto T. The biology of Interleukin-6. Blood 1989; 74: 1-10
  9. Buyalos RP, Funari VA, Azziz R, Watson JM, Martinez-Maza O. Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology. Feritil Steril 1992; 58: 302-6
  10. Gorospe WC, Hughes FM, Spangelo BL. Interleukin-6: Effects on and production by rat guanulosa cells in vitro. Endocrinology 1992; 130: 1750-2
  11. Jacobs AL, Sehgal PB, Julian J, Carson DD. Secretion and hormonal regulation of interleukin-6 production by mouse uterine stromal and polarized epithelial cells cultured in vitro. Endocrinology 1992; 131: 1037-45 https://doi.org/10.1210/en.131.1.45
  12. Tabibzadeh S. Human endometrium: An active site of cytokine production and action. Endocr Rev 1991; 12: 272-6
  13. Oppenheim JJ, Ruscetti FW, Faltynek C. Cytokines: in Stites DP, Terr AI (eds): Basic and Clinical immunology, de 7. East Norwalk, Appleton & lange 1991; 78-100
  14. Paolo Vercellini, Fabrizio De Benedetti, Edoardo Rossi, Alberto Colombo, Laura Trepidi, Pier G Crosignati. Tumor necrosis factor in plasma and peritoneal fluid of women with and without endometriosis. Gynecol Obstet Invest 1993; 36: 39-41
  15. Halme J, Becker S, Haskill S. Altered maturation and function of peritoneal macrophage: A new hypothesis for pathogenesis of endometriosis. Am J Obstet Gynecol 1987; 156: 783-9
  16. Tasuka Harada, Hiroki Yoshika, Souichi Yoshida, Tomio Iwabe, Yoshimasa Onohara, Mashahiro Tanikawa. Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. Am J Gynecol 1997; 176: 593-7
  17. Markowska J, Kowalska M, Gogacz M. Cytokines and endometriosis. Clin Exp Obstet Gynecol 2004; 31: 269-70
  18. Koumantakis E, Matalliotakis I, Neonaki M, Froudarakis G, Georgoulias V. Soluble serum interleukin2 receptor, interleukin-l$\alpha$ in patients with endometriosis and in controls. Arch Gynecol Obstet 1994; 255: 107-12
  19. Koyama N, Matsuura K, Okamura H. Cytokines in the peritoneal fluid of patients with endometriosis. Int J Gynecol Obstet 1993; 43: 45-50 https://doi.org/10.1016/0020-7292(93)90273-Y
  20. Nasir Rana, Domald P. Braun, Robert House, Howard Gebel, Carlos Rotman, Paul Dmowski. Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil Steril 1996; 65: 925-30
  21. Braun DP, Gebel H, House R, Rana N, Dmowski NP. Spontaneous and induced synthesis of cytokines by peritoneal blood monocytes in patients with endometriosis. Fertil Steril 1996; 65: 1125-9
  22. Suginami H, Yano K, Watanabe K. A factor inhibiting ovum capture by the oviductal fimbrial present in endometriosis peritoneal fluid. Fertil Stertil 1986; 46: 1140-6
  23. Iwabe T, Harada T, Terakawa N. Role of cytokines in endometriosis-associated infertility. Gynecol Obstet Invest 2002; 53: 19-25
  24. Weed JC, Arguembourg PC. Endometriosis. Can in produce an autoimmune response resulting infertility- Clin Obstet Gynecol 1989; 23: 885-9
  25. Olive DL, Montoya I, Riehl RM, Schenken RS. Macrophage-conditioned media enhance endometrial stromal cell proliferation in vitro. Am J Obstet Gynecol 1991; 41: 953-8
  26. Liu Y, Luo L, Zhao H. Changes of cytokines levels in peritoneal fluids of patients with endometriosis and its effect on reproductive activity. J Tongji Med Univ 2000; 20: 163-5
  27. Koga K, Osuga, Y, Yoshino O. Elevated interleukin-6 levels in the peritoneal fluid of women with endometriosis may be a mechanism for inflammatory reactions associated with endometriosis. Fertil Steril 2005; 83: 878-82
  28. Schroder W, Gaetje R, Baumann R. Interleukin-6 and soluble interleukin-6 receptor in peritoneal fluid and serum of patients with endometriosis. Clin Exp Obst Gyn 1996; 23: 10-4