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.
Schenken RSEndometriosis. In: JR Scott, PJ Di Sain, CB Hammond , WN Spellacy, eds. Danforth’s Obstetrics and Gynecology. Baltimore, MD: Lippincott, Williams & Wilkins; 1999:669-675.
2.
Bulun SE, Adashi EYThe 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.
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.
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.
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.
6.
Oosterlynck DJ , Cornillie FJ, Waer M., Koninckx PRImmunohistochemical characterization of leucocyte subpopulations in endometriotic lesions. Arch Gynecol Obstet . 1993;253(4):197-206.
7.
Cakmak H., Guzeloglu-Kayisli O., Kayisli UA, Arici A.Immune-endocrine interactions in endometriosis. Front Biosci . 2009;1: 429-443.
8.
Gazvani R., Templeton A.Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction. 2002;123(2):217-226.
Wu M-Y., Ho H-N.The role of cytokines in endometriosis. Am J Reprod Immunol . 2003;49(5):285-296.
11.
Minici F., Tiberi F., Tropea A., et al. Paracrine regulation of endometriotic tissue. Gynecol Endocrinol. 2007;23(10):574-580.
12.
Klinkova O. , Hansen KA, Winterton E., Mark CJ, Eyster KMTwo-way communication between endometrial stromal cells and monocytes. Reprod Sci. 2010 ;17(2):125-135.
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.
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.
15.
Eyster KM, Klinkova O., Kennedy V., Hansen KAWhole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium. Fertil Steril. 2007;88(6):1505-1533.
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.
17.
Yauk CL, Berndt ML, Williams A., Douglas GRComprehensive comparison of six microarray technologies. Nucleic Acids Res. 2004;32(15):e124.
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.
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.
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.
21.
Cox KE, Piva M., Sharpe-Timms KLDifferential regulation of matrix metalloproteinase-3 gene expression in endometriotic lesions compared with endometrium. Biol Reprod. 2001;65(4): 1297-1303.
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.
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.
24.
Chen C.-C, Lau LFFunctions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol.2009;41(4): 771-783.
25.
Leask A., Abraham DJThe role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol. 2003;81(6):355-363.
26.
Gressner OA , Gressner AMConnective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int. 2008;28(8):1065-1079.
27.
Absenger Y. , Hess-Stumpp H., Kreft B., et al. Cyr61, a deregulated gene in endometriosis . Mol Hum Reprod. 2004;10(6):399-407.
28.
Gashaw I., Hastings JM, Jackson KS, Winterhager E., Fazleabas ATInduced 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.
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.
30.
Harrington DJ, Lessey BA, Rai V., et al. Tenascin is differentially expressed in endometrium and endometriosis. J Pathol. 1999; 187(2):242-248.
31.
Chiquet-Ehrismann R.Molecules in focus: tenascins. Int J Biochem Cell Biol. 2004;36(6):986-990.
32.
Orend G., Chiquet-Ehrismann R.Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244(2):143-163.
33.
Hulboy DL, Rudolph LA, Matrisian LMMatrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod. 1997;3(1):27-45.
34.
McCawley LJ , Matrisian LMMatrix metalloproteinases: they’re not just for matrix anymore!. Curr Opin Cell Biol. 2001;13(5): 534-540.
35.
Bruner KL, Matrisian LM, Rodgers WH, Gorstein F., Osteen KGSuppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997;99(12):2851-2857.
36.
Raman D., Baugher PJ, Thu YM, Richmond A.Role of chemokines in tumor growth. Cancer Lett. 2007;256(2): 137-165.
37.
Mukaida N.Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol. 2003;284(4):L566-L577.
38.
Zhu YM, Woll PJMitogenic effects of interleukin-8/CXCL8 on cancer cells. Future Oncol. 2005;1(5):699-704.
39.
Keeley EC, Mehrad B., Strieter RMChemokines as mediators of neovascularization. Arterioscler Thromb Vasc Biol. 2008;28(11): 1928-1936.
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.
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.
42.
Arici A., Head JR, MacDonald PC, Casey MLRegulation of interleukin-8 gene expression in human endometrial cells in culture. Mol Cell Endocrinol. 1993;94(2):195-204.
43.
Stokes DLKeeping calcium in its place: Ca(2+)-ATPase and phospholamban. Curr Opin Struc Biol. 1997;7(4):550-556.
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.
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.
46.
Rizzuto R., Pinton P., Ferrari D., et al. Calcium and apoptosis: facts and hypotheses. Oncogene. 2003;22(53):8619-8627.
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.
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.
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.
51.
Lessey BA, Young SLIntegrins and other cell adhesion molecules in endometrium and endometriosis . Semin Reprod Endocrinol. 1997;15(3):291-299.
52.
Juliano RLSignal 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.
53.
Ramsay AG, Marshall JF, Hart IRIntegrin trafficking and its role in cancer metastasis. Cancer Metastasis Rev. 2007;26(3-4):567-578.
54.
Rai V., Hopkisson J., Kennedy S., Bergqvist A., Barlow DH, Mardon HJIntegrins alpha 3 and alpha 6 are differentially expressed in endometrium and endometriosis. J Pathol. 1996;180(2):181-187.
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.
