The Broad-Spectrum Chemokine Inhibitor NR58-3.14.3 Suppresses the Implantation and Survival of Human Endometrial Implants in the Nude Mice Endometriosis Model

Many chemokines likely contribute to the pathogenesis of endometriosis. The authors hypothesize that the broad-spectrum chemokine inhibitor NR58-3.14.3 may prevent ectopic human endometrium implantation and growth. After placing human endometrium fragments into the peritoneal cavity, ovariectomized athymic nude mice (n = 31) receiving intramuscular estradiol valerate were randomly assigned to daily intraperitoneal injections of either phosphate-buffered saline or NR58-3.14.3. Fourteen days later, the implant number and volume, proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase (TdT)—mediated dUTP nick end-labeling (TUNEL) index, and MTT cell viability were assessed in the implants. NR58-3.14.3 reduced the total number (45%) and total volume (81%) of endometriotic lesions (P < .05) and revealed a lower PCNA and higher TUNEL index in ectopic implants compared with controls (P < .05). NR58-3.14.3 treatment did not affect endometrial cell proliferation in vitro. NR58-3.14.3, by possibly regulating cell survival, can reduce the number and size of ectopic implants in vivo, supporting the potential use of chemokine inhibitors in novel therapies for endometriosis. Similar content being viewed by others

Ryan IP, Tseng JF, Schriock ED, Khorram O., Landers DV, Taylor RN Interleukin-8 concentrations are elevated in peritoneal fluid of women with endometriosis. Fertil Steril. 1995;63:929–932. Arici A., Tazuke SI, Attar E., Kliman HJ, Olive DL Interleukin-8 concentration in peritoneal fluid of patients with endometriosis and modulation of interleukin-8 expression in human mesothelial cells. Mol Hum Reprod. 1996;2:40–45. Taketani Y., Kuo TM, Mizuno M. Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosis. Am J Obstet Gynecol. 1992;167:265–270. Bhanoori M., Babu KA, Deenadayal M., Kennedy S., Shivaji S. The interleukin-6—174G/C promoter polymorphism is not associated with endometriosis in South Indian women. J Soc Gynecol Investig. 2005;12:365–369. Vernet-Tomas Mdel M., Perez-Ares CT, Verdu N., Fernandez-Figueras MT, Molinero JL, Carreras R. The depolarized expression of the alpha-6 integrin subunit in the endometria of women with endometriosis. J Soc Gynecol Investig. 2006; 13:292–296. Reckless J., Grainger DJ Identification of oligopeptide sequences which inhibit migration induced by a wide range of chemokines. Biochem J. 1999;340:803–811. Reckless J., Tatalick LM, Grainger DJ The pan-chemokine inhibitor NR58-3.14.3 abolishes tumour necrosis factor-alpha accumulation and leukocyte recruitment induced by lipopolysaccharide in vivo. Immunology. 2001;103:244–254. Arici A., Seli E., Zeyneloglu HB, Senturk LM, Oral E., Olive DL Interleukin-8 induces proliferation of endometrial stromal cells: a potential autocrine growth factor.J Clin Endocrinol Metab. 1998;83:1201–1205. Lin YJ, Lai MD, Lei HY, Wing LY Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology. 2006;147:1278–1286. Yang Y., Degranpre P., Kharfi A., Akoum A. Identification of macrophage migration inhibitory factor as a potent endothelial cell growth-promoting agent released by ectopic human endometrial cells. J Clin Endocrinol Metab. 2000;85:4721–4727. Attia MA, Weiss DW Immunology of spontaneous mammary carcinomas in mice. V. Acquired tumor resistance and enhancement in strain A mice infected with mammary tumor virus. Cancer Res. 1966;26:1787–1800. Kayisli UA, Aksu CA, Berkkanoglu M., Arici A. Estrogenicity of isoflavones on human endometrial stromal and glandular cells. J Clin Endocrinol Metab. 2002;87:5539–5544. Ulukus M., Cakmak H., Arici A. The role of endometrium in endometriosis. J Soc Gynecol Investig. 2006;13:467–476. Seli E., Berkkanoglu M., Arici A. Pathogenesis of endometriosis. Obstet Gynecol Clin North Am. 2003;30:41–61. Hill JA, Anderson DJ Lymphocyte activity in the presence of peritoneal fluid from fertile women and infertile women with and without endometriosis. Am J Obstet Gynecol. 1989;161: 861–864. Khorram O., Taylor RN, Ryan IP, Schall TJ, Landers DV Peritoneal fluid concentrations of the cytokine RANTES correlate with the severity of endometriosis. Am J Obstet Gynecol. 1993;169:1545–1549. Garcia-Velasco JA, Arici A. Interleukin-8 stimulates the adhesion of endometrial stromal cells to fibronectin. Fertil Steril. 1999;72:336–340. Arici A. Local cytokines in endometrial tissue: the role of interleukin-8 in the pathogenesis of endometriosis. Ann N Y Acad Sci. 2002;955:101–109. Mulayim N., Savlu A., Guzeloglu-Kayisli O., Kayisli UA, Arici A. Regulation of endometrial stromal cell matrix metalloproteinase activity and invasiveness by interleukin-8. Fertil Steril. 2004;81:904–911. Beech JS, Reckless J., Mosedale DE, Grainger DJ, Williams SC, Menon DK Neuroprotection in ischemia-reperfusion injury: an antiinflammatory approach using a novel broad-spectrum chemokine inhibitor. J Cereb Blood Flow Metab. 2001;21: 683–689. Naidu BV, Farivar AS, Krishnadasan B., et al. Broad-spectrum chemokine inhibition ameliorates experimental obliterative bronchiolitis. Ann Thorac Surg. 2003;75:1118–1122. 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;99:2851–2857. Zamah NM, Dodson MG, Stephens LC, Buttram VC Jr, Besch PK, Kaufman RH Transplantation of normal and ectopic human endometrial tissue into athymic nude mice. Am J Obstet Gynecol. 1984;149:591–597. Akoum A., Kong J., Metz C., Beaumont MC Spontaneous and stimulated secretion of monocyte chemotactic protein-1 and macrophage migration inhibitory factor by peritoneal macrophages in women with and without endometriosis. Fertil Steril. 2002;77:989–994. Akoum A., Lemay A., McColl SR, Paradis I., Maheux R. Increased monocyte chemotactic protein-1 level and activity in the peripheral blood of women with endometriosis. Le Groupe d’Investigation en Gynecologie. Am J Obstet Gynecol. 1996;175:1620–1625. McLaren J., Prentice A., Charnock-Jones DS, et al. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996;98:482–489. McLaren J., Prentice A., Charnock-Jones DS, Smith SK Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod. 1996;11:220–223. Iwabe T., Harada T., Tsudo T., et al.Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab. 2000;85:824–829. Uygur D., Aytan H., Zergeroglu S., Batioglu S. Leflunomide— an immunomodulator—induces regression of endometrial explants in a rat model of endometriosis.J Soc Gynecol Investig. 2006;13:378–383. Author information Authors and Affiliations Corresponding author Additional information The work was supported by a research grant from Biomeasure Inc. Part of this study was presented at the 59th Annual Meeting of the American Society for Reproductive Medicine, October 11–15, 2003, San Antonio, Texas. Rights and permissions About this article Cite this article Kayisli, U.A., Berkkanoglu, M., Zhang, L. et al. The Broad-Spectrum Chemokine Inhibitor NR58-3.14.3 Suppresses the Implantation and Survival of Human Endometrial Implants in the Nude Mice Endometriosis Model. Reprod. Sci. 14, 825–835 (2007). https://doi.org/10.1177/1933719107305865 Published: Issue date: DOI: https://doi.org/10.1177/1933719107305865