Abstract
Purpose
Inflammatory mediators, including chemokines, may play crucial roles in the development of endometriosis. Therefore, we investigated the expression and localization of CXCL16 and its receptor, CXCR6, in ovarian endometriotic tissues. We also examined whether CXCL16 induces IL-8 production in endometriotic stromal cells.
Methods
We performed immunohistochemical and Western blotting analyses of in vivo and in vitro samples. IL-8 production was assayed using an ELISA.
Results
Both CXCL16 and CXCR6 were expressed by endometriotic epithelial cells and stromal cells, but not normal ovarian stroma. A Western blotting analysis using primary cultured endometriotic stromal cells showed a constant expression of CXCL16 and CXCR6 in the proliferative phase, secretory phase and during gonadotropin-releasing hormone agonist therapy. CXCL16 induced IL-8 production in several endometriotic stromal cells in vitro.
Conclusions
CXCL16 and CXCR6 might be involved in the pathophysiology of endometriosis through regulation of the inflammatory response.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Endometriosis is a common gynecologic disease which affects 0.5–5% of fertile females and 25–40% of infertile females of reproductive age [1]. Endometriosis is defined as the ectopic growth of endometrium-like tissue in locations outside the uterus, including the ovaries and the pelvic peritoneum, and is an enigmatic disease that deteriorates the health of patients by causing pain, infertility, and adnexal masses. Sampson’s theory of implantation of endometrial cells [2] and fragments refluxed during the menstrual period is widely accepted [3]. In addition, a large volume of evidence indicates that inflammatory mediators and immune responses play crucial roles in the development of endometriosis and endometriosis-related pain and infertility [4, 5], although the pathophysiology of endometriosis is not fully understood.
Several studies have reported increased levels of many chemokines in the peritoneal fluid of patients with endometriosis. The majority of such chemokines are induced upon cellular activation by inflammatory stimulation [6–8]. The chemokine superfamily consists of about 50 cytokine members and 20 chemokine receptors [9, 10] involved in the regulation of tumor-associated immunity, blood vessel formation, cancer cell proliferation and metastasis. Over the past few years, there has been emerging evidence that several pairs of chemokines and their receptors play critical roles in the ontogenesis of endometriosis [11, 12].
Recently, CXCL16 has been identified to be a ligand for a chemokine receptor, CXCR6, which is expressed by several types of inflammatory cells, including peripheral blood leukocytes and macrophages [13–16]. CXCL16 exists in both transmembrane and soluble forms and functions as a scavenger receptor for oxidized lipoproteins and bacteria [17–19]. The expression of CXCL16 has been reported on immune cells like dendritic cells, macrophages, B cells, T cells, and on smooth muscle cells and endothelial cells [17–20], and therefore, it is associated with a number of human inflammatory diseases including rheumatoid arthritis [21, 22], interstitial lung disease [23, 24], and atherosclerosis [25–27].
In the present study, we examined the expression and localization of CXCL16 and CXCR6 in endometriotic ovarian cysts. We also examined whether CXCL16 is able to induce the production of interleukin-8 (IL-8), which has been considered a key molecule underlying endometriosis-related inflammation, in primary cultured endometriotic stromal cells. Our observation raised the possibility that CXCL16/CXCR6 might be involved in the pathophysiology of endometriosis.
Materials and methods
Patients
The endometriotic tissues used for this study were taken from the chocolate cyst linings of the ovaries of patients with endometriosis [n = 11; proliferative phase (n = 4), secretory phase (n = 4), and during gonadotropin-releasing hormone agonist (GnRHa) therapy (n = 3)] who had undergone surgery at Nagoya University Hospital. For all of these samples, informed consent was obtained from each patient before the study; this study was approved by the ethics committee of Nagoya University Graduate School of Medicine.
Immunohistochemistry
The immunohistochemical analyses were performed as described previously [28]. Briefly, formalin-fixed, paraffin embedded tissue sections were cut, deparaffinized, and treated at 90°C in a microwave oven for heat-induced epitope retrieval. Immunohistochemical staining was carried out based on the labeled streptavidin-biotin method after incubation with 10% normal rat serum in PBS for 10 min. The primary antibody against CXCL16 (Human CXCL16 Antibody, R&D System Inc., Minneapolis, MN, USA) or CXCR6 (ab8023, Abcam Inc., Cambridge, MA, USA) was diluted 1:100 in PBS. In negative control experiments, the primary antibody was replaced with rabbit IgG. The slides were counterstained with hematoxylin prior to mounting. Staining for CXCL16 and CXCR6 was carried out repeatedly for each sample. Stained sections were observed under an Olympus BH2 microscope (Tokyo, Japan) and photographed using a charge-couple device color camera (CS600; Olympus).
Primary culture of endometriotic stromal cells
Endometriotic stromal cells (ESCs) and endometrial stromal cells were separated as described previously [29]. In brief, endometriotic cysts and endometrial tissue in the late proliferative phase was minced into small pieces (~1 mm3), and these pieces were filtered through a cell strainer consisting of a 100 μm pore size nylon mesh (Becton Dickinson, Franklin Lakes, NJ, USA) to remove the blood cells. Then, the minced tissue was incubated with stirring at 37°C for 20 min in PBS and 0.5% collagenase (Wako, Osaka, Japan). The tissue digest was vigorously pipetted and passed over a cell strainer consisting of 70-μm pore size nylon mesh (Becton Dickinson). The ESCs collected from the lower receptacle were suspended and plated onto 60 mm sterile dishes. The ESCs were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Sigma, St. Louis, MO, USA) containing 10% fetal bovine serum (FCS) (Sigma), 100 IU/mL penicillin, and 100 μg/mL streptomycin. The purity of ESCs was assessed by morphological determination using light microscopy. Each cell population was routinely 98% pure, as assessed by phase contrast microscopy.
Western blotting analysis
Cultured ESCs within three times of passage and minced normal ovarian cortex were lysed in a radioimmunoprecipitation buffer (10 mM Tris–HCl, pH 7.4, 150 mM NaCl, 1% Nonidet P-40, 5 mM EDTA, 1% sodium deoxycholate, 0.1% SDS, 1.2% aprotinin, 5 μM leupeptine, 4 μM antipain, 1 mM phenylmethylsulfonylfluoride, and 0.1 mM Na3VO4). Cell lysates were clarified by centrifugation at 13,000×g at 4°C for 15 min, diluted in 2× sample buffer (125 mM Tris–HCl, pH 6.8, 4% SDS, 10% glycerol, 0.2% bromphenol blue, and 4% 2-mercaptoethanol), resolved by 10% SDS-PAGE, and immunoblotted with a 1:1,000 dilution of an anti-CXCL16 Ab, anti-CXCR6 Ab, or anti-β-actin Ab (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA).
ELISA for IL-8
The ESCs were diluted with DMEM with 10% FBS to a seeding density of 1 × 105 cells per well and suspended in 24-well tissue culture plates (500 μL/well). The cultures were allowed to proliferate until subconfluence (24–48 h). After 24 h serum starvation, CXCL16 (200 ng/mL; PeproTech, Rocky Hill, NJ, USA) was added and cells were incubated for another 24 h. The concentration of IL-8 in the culture supernatants was determined in duplicate using commercially available IL-8 ELISA kits (Quantikine Human CXCL8/IL-8 Immunoasay; R&D System Inc.). The intra- and inter-assay CV was 4.4–4.7 and 5.2–8.1%, respectively.
Results
CXCL16 and CXCR6 expression in ovarian endometriotic tissue
First, to confirm the expression of CXCL16 and CXCR6 in the ovarian endometriotic tissues, a Western blot analysis and an immunohistochemical analysis were performed. Table 1 shows the patient characteristics. The immunohistochemical analysis revealed that both CXCL16 and CXCR6 were expressed by endometriotic epithelial cells and stromal cells, but not normal ovarian stroma (Fig. 1). No obvious differences in the localization or intensity of staining were found among the samples from the proliferative phase, secretory phase and during GnRHa therapy (data not shown). Both CXCL16 and CXCR6 were detected in the primary cultured ESCs by a Western blotting analysis. The immunoreactive bands of CXCL16 and CXCR6 were conspicuous and had almost constant expression in ESCs from the proliferative phase (P1–P4), secretory phase (S1–S4), and during GnRHa therapy (G1–G3; Fig. 2). Both CXCL16 and CXCR6 were negligible in the normal ovarian cortex (Ov; Fig. 2). CXCL16, not CXCR6, in the physiological endometrial stromal cells showed a weaker immunoreactivity compared with those in ESCs (E; Fig. 2).
The effects of CXCL16 on IL-8 production by ESCs
Next, we investigated whether CXCL16 affects the IL-8 production of primary cultured ESCs. Measurement of IL-8 in culture supernatant by ELISA showed that 200 ng/mL CXCL16 increased the IL-8 production in the most of the cultured ESCs (P1, P2, S1, S2, S3, S4, G1, G2). However, a few of the cultured ESCs (P3, P4, G3) did not show an increase in IL-8 with CXCL16 (Fig. 3).
Discussion
In the present study, we first found that both CXCL16 and its receptor, CXCR6, are expressed in the epithelial cells and stromal cells in the ovarian endometriotic tissues. It has been reported that CXCR6 is expressed on several types of inflammatory cells, such as CD4+ T cells, CD8+ T cells [15], NKT cells [30], and NK cells [31]. On the other hand, CXCL16 has been reported to be expressed in activated endothelial cells [32], Hodgkin’s disease-derived tumor cells and tumor-associated macrophages in rectal cancer [33, 34]. It has recently been reported that CXCL16 and CXCR6 co-localized on prostate cancer cells and showed the highest expression in cancer cells surrounded by inflammatory stroma [35]. CXCL16 has been also demonstrated to stimulate the growth of prostate cancer cell lines via CXCR6.
CXCL16 is synthesized as a transmembrane molecule that is transported to the cell surface. There are two forms of CXCL16 resulting from cleavage at the cell surface [17, 19]. The soluble form of CXCL16 functions as chemoattractant to promote cell migration [36]. The remaining transmembrane CXCL16 can function as a cell adhesion molecule for cells expressing CXCR6 [17, 19], and has also been demonstrated to function as a novel scavenger receptor for phosphatidylserine and oxidized lipoprotein [18]. Studies using inhibitors revealed that the two disintegrin-like metalloproteinases, ADAM10 and ADAM17, are mainly involved in this release of CXCL16 [37, 38]. ADAM10 has been reported to be expressed by endometrial epithelial cells and stromal cells and a higher expression of ADAM10 mRNA in epithelial and stromal cells of patients with endometriosis has been observed in comparison to patients without endometriosis [39]. Recently, Baston-Büst et al. [40] reported that syndecan-1-knockdown decidualized human endometrial stromal cells showed a higher secretion of chemokines, including CXCL16 to the culture medium compared with wild-type endometrial stromal cell lines. Based on both previous findings and our present results, the expression of CXCL16 by endometrial and endometriotic stromal cells might thus be regulated by inflammatory response. However, our results also showed that GnRHa treatment did not affect the expression of CXCL16 and CXCR6 in ESCs in vitro. An extended culture of these cells might impair their properties and, therefore our results might not reflect the actual situation in vivo.
It is generally believed that local inflammation occurs in the peritoneal cavity in endometriosis and therefore, affects immunological and inflammatory factors, which play an important role in the pathogenesis of endometriosis [4]. IL-8 is an angiogenic, proinflammatory and growth-inducing cytokine [41]. IL-8 has also been reported to be produced in the human endometrium in vivo, and that IL-8 induces the proliferation of endometrial stromal cells as an autocrine growth factor [42]. Moreover, Iwabe et al. [7] demonstrated that tumor necrosis factor-α stimulates the proliferation of endometriotic stromal cells through induction of IL-8 gene and protein expression. Our current results showed that CXCL16 may induce IL-8 production in ESCs. Taken together, the CXCL16 expressed by endometriotic tissues might be involved in the inflammatory aspect of endometriosis though the increase in IL-8 production.
In conclusion, we have herein demonstrated that CXCL16 and CXCR6 are expressed by ovarian endometriotic tissues in vitro and in vivo, and that CXCL16 induces IL-8 production in endometriotic stromal cells. Therefore, CXCL16 and CXCR6 might be key molecules involved in the regulation of the inflammatory response and proliferation in endometriosis. Further studies will be required to provide a more detailed functional evaluation of CXCL16 and CXCR6 in endometriosis and to elucidate the pathophysiology of endometriosis.
References
Ozkan S, Murk W, Arici A (2008) Endometriosis and infertility: epidemiology and evidence-based treatments. Ann N Y Acad Sci 1127:92–100. doi:1127/1/92[pii]10.1196/annals.1434.007
Sampson JA (1927) Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 3(2):93–110 143
de Ziegler D, Borghese B, Chapron C (2010) Endometriosis and infertility: pathophysiology and management. Lancet 376(9742):730–738. doi:S0140-6736(10)60490-4[pii]10.1016/S0140-6736(10)60490-4
Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung D (2006) Is endometriosis associated with systemic subclinical inflammation? Gynecol Obstet Invest 62(3):139–147. doi:000093121[pii]10.1159/000093121
Osuga Y (2008) Novel therapeutic strategies for endometriosis: a pathophysiological perspective. Gynecol Obstet Invest 66(Suppl 1):3–9. doi:000148025[pii]10.1159/000148025
Akoum A, Lemay A, Brunet C, Hebert J (1995) Secretion of monocyte chemotactic protein-1 by cytokine-stimulated endometrial cells of women with endometriosis Le groupe d’investigation en gynecologie. Fertil Steril 63(2):322–328
Iwabe T, Harada T, Tsudo T, Nagano Y, Yoshida S, Tanikawa M, Terakawa N (2000) Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab 85(2):824–829
Tseng JF, Ryan IP, Milam TD, Murai JT, Schriock ED, Landers DV, Taylor RN (1996) Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis. J Clin Endocrinol Metab 81(3):1118–1122
Luster AD (1998) Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 338(7):436–445. doi:10.1056/NEJM199802123380706
Struyf S, Proost P, Van Damme J (2003) Regulation of the immune response by the interaction of chemokines and proteases. Adv Immunol 81:1–44
Chand AL, Murray AS, Jones RL, Hannan NJ, Salamonsen LA, Rombauts L (2007) Laser capture microdissection and cDNA array analysis of endometrium identify CCL16 and CCL21 as epithelial-derived inflammatory mediators associated with endometriosis. Reprod Biol Endocrinol 5:18. doi:1477-7827-5-18[pii]10.1186/1477-7827-5-18
Lin YJ, Lai MD, Lei HY, Wing LY (2006) Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology 147(3):1278–1286. doi:en.2005-0790[pii]10.1210/en.2005-0790
Hase K, Murakami T, Takatsu H, Shimaoka T, Iimura M, Hamura K, Kawano K, Ohshima S, Chihara R, Itoh K, Yonehara S, Ohno H (2006) The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and M cells mediates lympho-epithelial interaction in GALT. J Immunol 176(1):43–51. doi:176/1/43[pii]
Heydtmann M, Lalor PF, Eksteen JA, Hubscher SG, Briskin M, Adams DH (2005) CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J Immunol 174(2):1055–1062. doi:174/2/1055[pii]
Kim CH, Kunkel EJ, Boisvert J, Johnston B, Campbell JJ, Genovese MC, Greenberg HB, Butcher EC (2001) Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J Clin Invest 107(5):595–601. doi:10.1172/JCI11902
Tabata S, Kadowaki N, Kitawaki T, Shimaoka T, Yonehara S, Yoshie O, Uchiyama T (2005) Distribution and kinetics of SR-PSOX/CXCL16 and CXCR6 expression on human dendritic cell subsets and CD4+ T cells. J Leukoc Biol 77(5):777–786. doi:jlb.1204733[pii]10.1189/jlb.1204733
Matloubian M, David A, Engel S, Ryan JE, Cyster JG (2000) A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat Immunol 1(4):298–304. doi:10.1038/79738
Shimaoka T, Kume N, Minami M, Hayashida K, Kataoka H, Kita T, Yonehara S (2000) Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem 275(52):40663–40666. doi:10.1074/jbc.C000761200C000761200[pii]
Wilbanks A, Zondlo SC, Murphy K, Mak S, Soler D, Langdon P, Andrew DP, Wu L, Briskin M (2001) Expression cloning of the STRL33/BONZO/TYMSTR ligand reveals elements of CC, CXC, and CX3C chemokines. J Immunol 166(8):5145–5154
Shashkin P, Simpson D, Mishin V, Chesnutt B, Ley K (2003) Expression of CXCL16 in human T cells. Arterioscler Thromb Vasc Biol 23(1):148–149
Nanki T, Shimaoka T, Hayashida K, Taniguchi K, Yonehara S, Miyasaka N (2005) Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum 52(10):3004–3014. doi:10.1002/art.21301
Ruth JH, Haas CS, Park CC, Amin MA, Martinez RJ, Haines GK 3rd, Shahrara S, Campbell PL, Koch AE (2006) CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Arthritis Rheum 54(3):765–778. doi:10.1002/art.21662
Agostini C, Cabrelle A, Calabrese F, Bortoli M, Scquizzato E, Carraro S, Miorin M, Beghe B, Trentin L, Zambello R, Facco M, Semenzato G (2005) Role for CXCR6 and its ligand CXCL16 in the pathogenesis of T-cell alveolitis in sarcoidosis. Am J Respir Crit Care Med 172(10):1290–1298. doi:200501-142OC[pii]10.1164/rccm.200501-142OC
Morgan AJ, Guillen C, Symon FA, Huynh TT, Berry MA, Entwisle JJ, Briskin M, Pavord ID, Wardlaw AJ (2005) Expression of CXCR6 and its ligand CXCL16 in the lung in health and disease. Clin Exp Allergy 35(12):1572–1580. doi:CEA2383[pii]10.1111/j.1365-2222.2005.02383.x
Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H, Moriwaki H, Kataoka H, Nishi E, Horiuchi H, Arai H, Yokode M (2001) Role of oxidized LDL in atherosclerosis. Ann N Y Acad Sci 947:199–205 discussion 205–196
Sheikine Y, Hansson GK (2004) Chemokines and atherosclerosis. Ann Med 36(2):98–118
Wuttge DM, Zhou X, Sheikine Y, Wagsater D, Stemme V, Hedin U, Stemme S, Hansson GK, Sirsjo A (2004) CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions. Arterioscler Thromb Vasc Biol 24(4):750–755. doi:10.1161/01.ATV.0000124102.11472.3601.ATV.0000124102.11472.36[pii]
Iwase A, Ando H, Nagasaka T, Goto M, Harata T, Kikkawa F (2007) Distribution of endothelin-converting enzyme-1 and neutral endopeptidase in human endometrium. J Histochem Cytochem 55(12):1229–1235. doi:jhc.7A7274.2007[pii]10.1369/jhc.7A7274.2007
Iwase A, Ando H, Nagasaka T, Shibata D, Harata T, Shimomura Y, Goto M, Kikkawa F (2006) Neutral endopeptidase expressed by decidualized stromal cells suppresses akt phosphorylation and deoxyribonucleic acid synthesis induced by endothelin-1 in human endometrium. Endocrinology 147(11):5153–5159. doi:en.2006-0172[pii]10.1210/en.2006-0172
Kim CH, Johnston B, Butcher EC (2002) Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity. Blood 100(1):11–16. doi:10.1182/blood-2001-12-0196
Unutmaz D, Xiang W, Sunshine MJ, Campbell J, Butcher E, Littman DR (2000) The primate lentiviral receptor Bonzo/STRL33 is coordinately regulated with CCR5 and its expression pattern is conserved between human and mouse. J Immunol 165(6):3284–3292. doi:ji_v165n6p3284[pii]
Volin MV, Woods JM, Amin MA, Connors MA, Harlow LA, Koch AE (2001) Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol 159(4):1521–1530. doi:S0002-9440(10)62537-0[pii]10.1016/S0002-9440(10)62537-0
Hanamoto H, Nakayama T, Miyazato H, Takegawa S, Hieshima K, Tatsumi Y, Kanamaru A, Yoshie O (2004) Expression of CCL28 by Reed-Sternberg cells defines a major subtype of classical Hodgkin’s disease with frequent infiltration of eosinophils and/or plasma cells. Am J Pathol 164(3):997–1006. doi:S0002-9440(10)63187-2[pii]10.1016/S0002-9440(10)63187-2
Wagsater D, Dimberg J (2004) Expression of chemokine receptor CXCR6 in human colorectal adenocarcinomas. Anticancer Res 24(6):3711–3714
Darash-Yahana M, Gillespie JW, Hewitt SM, Chen YY, Maeda S, Stein I, Singh SP, Bedolla RB, Peled A, Troyer DA, Pikarsky E, Karin M, Farber JM (2009) The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers. PLoS One 4(8):e6695 10.1371/journal.pone.0006695
Shimaoka T, Nakayama T, Fukumoto N, Kume N, Takahashi S, Yamaguchi J, Minami M, Hayashida K, Kita T, Ohsumi J, Yoshie O, Yonehara S (2004) Cell surface-anchored SR-PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6-expressing cells. J Leukoc Biol 75(2):267–274. doi:10.1189/jlb.1003465jlb.1003465[pii]
Abel S, Hundhausen C, Mentlein R, Schulte A, Berkhout TA, Broadway N, Hartmann D, Sedlacek R, Dietrich S, Muetze B, Schuster B, Kallen KJ, Saftig P, Rose-John S, Ludwig A (2004) The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol 172(10):6362–6372
Gough PJ, Garton KJ, Wille PT, Rychlewski M, Dempsey PJ, Raines EW (2004) A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16. J Immunol 172(6):3678–3685
Finas D, Huszar M, Agic A, Dogan S, Kiefel H, Riedle S, Gast D, Marcovich R, Noack F, Altevogt P, Fogel M, Hornung D (2008) L1 cell adhesion molecule (L1CAM) as a pathogenetic factor in endometriosis. Hum Reprod 23(5):1053–1062. doi:den044[pii]10.1093/humrep/den044
Baston-Bust DM, Gotte M, Janni W, Krussel JS, Hess AP (2010) Syndecan-1 knock-down in decidualized human endometrial stromal cells leads to significant changes in cytokine and angiogenic factor expression patterns. Reprod Biol Endocrinol 8:133. doi:1477-7827-8-133[pii]10.1186/1477-7827-8-133
Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089):1798–1801
Arici A, Seli E, Zeyneloglu HB, Senturk LM, Oral E, Olive DL (1998) Interleukin-8 induces proliferation of endometrial stromal cells: a potential autocrine growth factor. J Clin Endocrinol Metab 83(4):1201–1205
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Manabe, S., Iwase, A., Goto, M. et al. Expression and localization of CXCL16 and CXCR6 in ovarian endometriotic tissues. Arch Gynecol Obstet 284, 1567–1572 (2011). https://doi.org/10.1007/s00404-011-2002-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-011-2002-y