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Reciprocal Communication Between Endometrial Stromal Cells and Macrophages

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Abstract

This study tested the hypothesis that reciprocal communication occurs between macrophages and cultured human endometrial stromal cells and that this communication may contribute to the pathology of endometriosis. An endometrial stromal cell line (telomerase-immortalized human endometrial stromal cell [T-HESC]) was treated with macrophage-conditioned medium (CM) ± estradiol + progesterone. Macrophages were treated without or with T-HESC CM. DNA microarray identified 716 differentially expressed genes in T-HESCs in response to factors secreted by macrophages. Upregulated genes in T-HESC included interleukin 8 (IL-8)/chemokine (C-X-C motif) ligand 8 (CXCL8), matrix metalloproteinase 3 (MMP3), phospholamban, cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), tenascin C, and nicotinamide N-methyltransferase (NNMT), whereas integrin α-6 was downregulated. In contrast, 15 named genes were differentially expressed in macrophages in response to factors secreted by endometrial stromal cells. The data document reciprocal communication between macrophages and endometrial stromal cells and suggest that interaction with macrophages stimulates the expression of genes in endometrial stromal cells that may support the establishment of endometriosis.

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References

  1. Schenken RS. Endometriosis. In: JR Scott, PJ Di Sain, CB Hammond, WN Spellacy, eds. Danforth’s Obstetrics and Gynecology. Baltimore, MD: Lippincott, Williams & Wilkins; 1999:669–675.

    Google Scholar 

  2. Bulun SE, Adashi EY. The physiology and pathology of the female reproductive axis. In: HM Kronenberg, S Melmed, KS Polonsky, PR Larsen, eds. Williams Textbook of Endocrinology. Philadelphia, PA: Saunders Elsevier; 2008:541–614.

    Google Scholar 

  3. Christodoulakos G, Augoulea A, Lambrinoudaki I, Sioulas V, Creatsas G. Pathogenesis of endometriosis: the role of defective ‘immunosurveillance.’. Eur J Contracep Reprod Health Care. 2007;12(3):194–202.

    Article  CAS  Google Scholar 

  4. Khan KN, Kitajima M, Hiraki K, et al. Immunopathogenesis of pelvic endometriosis: role of hepatocyte growth factor, macrophages and ovarian steroids. Am J Reprod Immunol. 2008; 60(5):383–404.

    Article  CAS  PubMed  Google Scholar 

  5. Halme J, Becker S, Wing R. Accentuated cyclic activation of peritoneal macrophages in patients with endometriosis. Am J Obstet Gynecol. 1984;148(1):85–90.

    Article  CAS  PubMed  Google Scholar 

  6. Oosterlynck DJ, Cornillie FJ, Waer M, Koninckx PR. Immunohistochemical characterization of leucocyte subpopulations in endometriotic lesions. Arch Gynecol Obstet. 1993;253(4):197–206.

    Article  CAS  PubMed  Google Scholar 

  7. Cakmak H, Guzeloglu-Kayisli O, Kayisli UA, Arici A. Immuneendocrine interactions in endometriosis. Front Biosci. 2009;1: 429–443.

    Google Scholar 

  8. Gazvani R, Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction. 2002;123(2):217–226.

    Article  CAS  PubMed  Google Scholar 

  9. Bedaiwy MA, Falcone T. Peritoneal fluid environment in endometriosis. Clinicopathological implications. Minerva Ginecol. 2003;55(4):333–345.

    CAS  PubMed  Google Scholar 

  10. Wu M-Y, Ho H-N. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49(5):285–296.

    PubMed  Google Scholar 

  11. Minici F, Tiberi F, Tropea A, et al. Paracrine regulation of endometriotic tissue. Gynecol Endocrinol. 2007;23(10):574–580.

    Article  CAS  PubMed  Google Scholar 

  12. Klinkova O, Hansen KA, Winterton E, Mark CJ, Eyster KM. Two-way communication between endometrial stromal cells and monocytes. Reprod Sci. 2010;17(2):125–135.

    Article  PubMed  Google Scholar 

  13. Krikun G, Mor G, Alvero A, et al. A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology. 2004;145(5):2291–2296.

    Article  CAS  PubMed  Google Scholar 

  14. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. 1976;17(5):565–577.

    Article  CAS  PubMed  Google Scholar 

  15. Eyster KM, Klinkova O, Kennedy V, Hansen KA. Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium. Fertil Steril. 2007;88(6):1505–1533.

    Article  CAS  PubMed  Google Scholar 

  16. Radzun HJ, Parwaresch MR, Sundström C, Nilsson K, Eissner M. Monocytic origin of the human hematopoietic cell line U-937 and its convertibility to macrophages evidenced by isoenzyme mapping. Int J Cancer. 1983;31(2):181–186.

    Article  CAS  PubMed  Google Scholar 

  17. Yauk CL, Berndt ML, Williams A, Douglas GR. Comprehensive comparison of six microarray technologies. Nucleic Acids Res. 2004;32(15):e124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Shippy R, Sendera TJ, Lockner R, et al. Performance evaluation of commercial short-oligonucleotide microarrays and the impact of noise in making cross-platform correlations. BMC Genomics. 2004;5(1):61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Hellemans J, Mortier G, De Paepe A, Speleman F, Vandesompele J. qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol. 2007;8(2):R19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Brazma A, Hingamp P, Quackenbush J, et al. Minimum information about a microarray experiment (MIAME)—toward standards for microarray data. Nat Genet. 2001;29(4):365–371.

    Article  CAS  PubMed  Google Scholar 

  21. Cox KE, Piva M, Sharpe-Timms KL. Differential regulation of matrix metalloproteinase-3 gene expression in endometriotic lesions compared with endometrium. Biol Reprod. 2001;65(4): 1297–1303.

    Article  CAS  PubMed  Google Scholar 

  22. Harada T, Yoshioka H, Yoshida S, et al. Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. Am J Obstet Gynecol. 1997;176(3):593–597.

    Article  CAS  PubMed  Google Scholar 

  23. Nair AS, Nair HB, Lucidi RS, et al. Modeling the early endometriotic lesion: mesothelium-endometrial cell co-culture increases endometrial invasion and alters mesothelial and endometrial gene transcription. Fertil Steril. 2008;90(suppl 2):1487–1495.

    Article  PubMed  Google Scholar 

  24. Chen C-C, Lau LF. Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol. 2009;41(4): 771–783.

    Article  CAS  PubMed  Google Scholar 

  25. Leask A, Abraham DJ. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol. 2003;81(6):355–363.

    Article  CAS  PubMed  Google Scholar 

  26. Gressner OA, Gressner AM. Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int. 2008;28(8):1065–1079.

    Article  CAS  PubMed  Google Scholar 

  27. Absenger Y, Hess-Stumpp H, Kreft B, et al. Cyr61, a deregulated gene in endometriosis. Mol Hum Reprod. 2004;10(6):399–407.

    Article  CAS  PubMed  Google Scholar 

  28. Gashaw I, Hastings JM, Jackson KS, Winterhager E, Fazleabas AT. Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria. Biol Reprod. 2006;74(6):1060–1066.

    Article  CAS  PubMed  Google Scholar 

  29. Tan O, Ornek T, Seval Y, Sati L, Arici A. Tenascin is highly expressed in endometriosis and its expression is upregulated by estrogen. Fertil Steril. 2008;89(5):1082–1089.

    Article  CAS  PubMed  Google Scholar 

  30. Harrington DJ, Lessey BA, Rai V, et al. Tenascin is differentially expressed in endometrium and endometriosis. J Pathol. 1999; 187(2):242–248.

    Article  CAS  PubMed  Google Scholar 

  31. Chiquet-Ehrismann R. Molecules in focus: tenascins. Int J Biochem Cell Biol. 2004;36(6):986–990.

    Article  CAS  PubMed  Google Scholar 

  32. Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244(2):143–163.

    Article  CAS  PubMed  Google Scholar 

  33. Hulboy DL, Rudolph LA, Matrisian LM. Matrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod. 1997;3(1):27–45.

    Article  CAS  PubMed  Google Scholar 

  34. McCawley LJ, Matrisian LM. Matrix metalloproteinases: they’re not just for matrix anymore!. Curr Opin Cell Biol. 2001;13(5): 534–540.

    Article  CAS  PubMed  Google Scholar 

  35. Bruner KL, Matrisian LM, Rodgers WH, Gorstein F, Osteen KG. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997;99(12):2851–2857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Raman D, Baugher PJ, Thu YM, Richmond A. Role of chemokines in tumor growth. Cancer Lett. 2007;256(2): 137–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mukaida N. Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol. 2003;284(4):L566–L577.

    Article  CAS  PubMed  Google Scholar 

  38. Zhu YM, Woll PJ. Mitogenic effects of interleukin-8/CXCL8 on cancer cells. Future Oncol. 2005;1(5):699–704.

    Article  CAS  PubMed  Google Scholar 

  39. Keeley EC, Mehrad B, Strieter RM. Chemokines as mediators of neovascularization. Arterioscler Thromb Vasc Biol. 2008;28(11): 1928–1936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ulukus M, Ulukus EC, Tavmergen Goker EN, Tavmergen E, Zheng W, Arici A. Expression of interleukin-8 and monocyte chemotactic protein 1 in women with endometriosis. Fertil Steril. 2009;91(3):687–693.

    Article  CAS  PubMed  Google Scholar 

  41. Iwabe T, Harada T, Tsudo T, Tanikawa M, Onohara Y, Terakawa N. Pathogenetic significance of increased levels of interleukin-8 in the peritoneal fluid of patients with endometriosis. Fertil Steril. 1998;69(5):924–930.

    Article  CAS  PubMed  Google Scholar 

  42. Arici A, Head JR, MacDonald PC, Casey ML. Regulation of interleukin-8 gene expression in human endometrial cells in culture. Mol Cell Endocrinol. 1993;94(2):195–204.

    Article  CAS  PubMed  Google Scholar 

  43. Stokes DL. Keeping calcium in its place: Ca(2+)-ATPase and phospholamban. Curr Opin Struc Biol. 1997;7(4):550–556.

    Article  CAS  Google Scholar 

  44. Vafiadaki E, Papalouka V, Arvanitis DA, Kranias EG, Sanoudou D. The role of SERCA2a/PLN complex, Ca2+ homeostasis, and anti-apoptotic proteins in determining cell fate. Eur J Physiol. 2009;457(3):687–700.

    Article  CAS  Google Scholar 

  45. Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T, Tizzuto R. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J. 2001;20(11): 2690–2701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rizzuto R, Pinton P, Ferrari D, et al. Calcium and apoptosis: facts and hypotheses. Oncogene. 2003;22(53):8619–8627.

    Article  CAS  PubMed  Google Scholar 

  47. Aksoy S, Szumlanski CL, Weinshilboum RM. Human liver nicotinamide N-methyltransferase cDNA cloning, expression, and biochemical characterization. J Biol Chem. 1994;269(20): 14835–14840.

    CAS  PubMed  Google Scholar 

  48. Kim J, Hong SJ, Lim EK, et al. Expression of nicotinamide N-methyltransferase in hepatocellular carcinoma is associated with poor prognosis. J Exp Clin Cancer Res. 2009;28(1):20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Allegra A, Marino A, Coffaro F, et al. Is there a uniform basal endometrial gene expression profile during the implantation window in women who became pregnant in a subsequent ICSI cycle? Hum Reprod. 2009;24(10):2549–2557.

    Article  CAS  PubMed  Google Scholar 

  50. Wu Y, Siadaty MS, Berens ME, Hampton GM, Theodorescu D. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene. 2008;27(52):6679–6689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lessey BA, Young SL. Integrins and other cell adhesion molecules in endometrium and endometriosis. Semin Reprod Endocrinol. 1997;15(3):291–299.

    Article  CAS  PubMed  Google Scholar 

  52. Juliano RL. Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol. 2002;42:283–323.

    Article  CAS  PubMed  Google Scholar 

  53. Ramsay AG, Marshall JF, Hart IR. Integrin trafficking and its role in cancer metastasis. Cancer Metastasis Rev. 2007;26(3–4):567–578.

    Article  CAS  PubMed  Google Scholar 

  54. Rai V, Hopkisson J, Kennedy S, Bergqvist A, Barlow DH, Mardon HJ. Integrins alpha 3 and alpha 6 are differentially expressed in endometrium and endometriosis. J Pathol. 1996;180(2):181–187.

    Article  CAS  PubMed  Google Scholar 

  55. Vernet-Tomas Mdel M, Perez-Ares CT, Verdu N, Fernandez-Figueras MT, Carreras R. The depolarized expression of the alpha-6 integrin subunit in the endometria of women with endometriosis. J Soc Gynecol Investig. 2006;13(4):292–296.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Kathleen M. Eyster PhD.

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Eyster, K.M., Hansen, K.A., Winterton, E. et al. Reciprocal Communication Between Endometrial Stromal Cells and Macrophages. Reprod. Sci. 17, 809–822 (2010). https://doi.org/10.1177/1933719110371854

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