The aim of this study was to investigate the efficacy of anti-interleukin 6 (IL-6) therapy in the treatment of endometriosis in a rat model.
Study Design:
After the peritoneal implantation of autologous endometrial tissue, 22 Wistar female rats were divided to create 2 intervention groups: the tocilizumab group (n = 13) and the control group (n = 9). After measuring implant volume, saline was administered to the rats in the control group and 8 mg/kg tocilizumab was administered intraperitoneally to the rats in the tocilizumab-treated group every 2 weeks. After a 4-week treatment period, the volumes and histopathological properties of the implants were evaluated. A scoring system was used to evaluate the preservation of epithelia. Fibrosis score was assessed between the groups. Ectopic and eutopic endometrium were evaluated immunohistochemically for IL-6 and vascular endothelial growth factor (VEGF).
Results:
There was a significant difference between the volumes of implants before and after treatment in the tocilizumab group (P < .05). The posttreatment volumes of lesions were smaller in the tocilizumab group than in the control group. Histologic and fibrosis scores were lower in the tocilizumab group than in the control group. Immunoreactivity intensity for VEGF was significantly decreased in the tocilizumab group for ectopic and eutopic endometrium (P < .05). Interleukin 6 levels and endometrial thickness for ectopic and eutopic endometrium were similar between the groups.
Conclusion:
Tocilizumab treatment had a regressive effect on the endometriotic implants.
WickiewiczDChrobakAGmyrekGB. Diagnostic accuracy of interleukin-6 levels in peritoneal fluid for detection of endometriosis. Arch Gynecol Obstet. 2013;288(4):805–814.
2.
BischoffFZSimpsonJL. Heritability and molecular genetic studies of endometriosis. Hum Reprod Update. 2000;6(1):37–44.
3.
VelascoIAciénPCamposAAciénMIRuiz-MaciáE. Interleukin-6 and other soluble factors in peritoneal fluid and endometriomas and their relation to pain and aromatase expression. J Reprod Immunol. 2010;84(2):199–205.
4.
AciénPVelascoIGutiérrezMMartínez-BeltránM. Aromatase expression in endometriotic tissues and its relationship to clinical and analytical findings. Fertil Steril. 2007;88(1):32–38.
5.
LebovicDIMuellerMDHornungDTaylorRN. Immunology of endometriosis. Immunol Allergy Clin North Am. 2002;22(3):585–598.
6.
BedaiwyMAFalconeTSharmaRK. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod. 2002;17(2):426–431.
7.
Navarro-MillánISinghJACurtisJR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther. 2012;34(4):788–802.
8.
IslimyeMKilicSZulfikarogluETopcuOZergerogluSBatiogluS. Regression of endometrial autografts in a rat model of endometriosis treated with etanercept. Eur J Obstet Gynecol Reprod Biol. 2011;159(1):184–189.
9.
IsikHMoralogluOKilicSSevenACaydereMBatiogluS. A recombinant humanized monoclonal antibody for treatment of endometriosis in a rat model. J Endometr. 2011;3(3):143–150.
10.
KeenanJAWilliams-BoycePK. Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Fertil Steril. 1999;72(1):135–141.
11.
AnafVSimomPH. Relationship between Endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod. 2000;15(8):1744–1750.
12.
HughesEFedorkowDCollinsJVandekerckhoveP. Ovulation suppression for endometriosis. Cochrane Database Syst Rev. 2000;(2):CD000155.
13.
OthmanEERHornunDSaleHKhalifaEAEl-MetwallyTKAl-HendyA. Serum cytokines as biomarkers for nonsurgical prediction of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2008;137(2):240–246.
14.
MartinezSGarridoNCoperiasJL. Serum interleukin-6 levels are elevated in women with minimal-mild endometriosis. Hum Reprod. 2007;22(3):836–842.
15.
TsudoTHaradaTIwabeT. Altered gene expression and secretion of interleukin-6 in stromal cells derived from endometriotic tissues. Fertil Steril. 2000;73(2):205–211.
16.
HaradaTYoshiokaHYoshidaS. Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. Am J Obstet Gynecol. 1997;176(3):593–597.
17.
MahnkeJLDawoodMYHuangJC. Vascular endothelial growth factor and interleukin-6 in peritoneal fluid of women with endometriosis. Fertil Steril. 2000;73(1):166–170.
18.
PunnonenJTeisalaKRantaHBennettBPunnonenR. Increased levels of interleukin-6 and interleukin-10 in the peritoneal fluid of patients with endometriosis. Am J Obstet Gynecol. 1996;174(5):1522–1526.
19.
PurohitASinghAGhilchikMWSerlupi-CrescenziOReedMJ. Inhibition of IL-6+IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist, Sant 7, in breast tissue-derived fibroblasts. Br J Cancer. 2003;88(4):630–635.
20.
SinghAPurohitADuncanLJMokbelKGhilchickMWReedMJ. Control of aromatase activity in breast tumours: the role of the immune system. J. Steroid Biochem Mol Biol. 1997;61(3-6):185–192.
21.
BulunSEZeitounKTakayamaK. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer. 1999;6(2):293–301.
22.
SevketOSevketABuyukpinarbasiliN. The effects of ranibizumab on surgically induced endometriosis in a rat model: a preliminary study. Reprod Sci. 2013;20(10):1224–1229.
23.
CeyhanSTOnguruOFidanU. Comparison of aromatase inhibitor (letrozole) and immunomodulators (infliximab and etanercept) on the regression of endometriotic implants in a rat model. Eur J Obstet Gynecol Reprod Biol. 2011;154(1):100–104.
24.
BarrierBFBatesGWLelandMMLeachDARobinsonRDPropstAM. Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril. 2004;81(suppl 1):775–779.
25.
OzerHBoztosunAAçmazGAtilganRAkkarOBKosarMI. The efficacy of bevacizumab, sorafenib, and retinoic acid on rat endometriosis model. Reprod Sci. 2013;20(1):26–32.
26.
WangYvan Boxel-DezaireAHCheonHYangJStarkGR. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci U S A. 2013;110(42):16975–16980.
27.
KimBGYooJYKimTH. Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis. Hum Reprod. 2015;30(5):1069–1078.
28.
O’DonnellJLJoyceMRShannonAMHarmeyJGeraghtyJBouchier-HayesD. Oncological implications of hypoxia inducible factor-1alpha (HIF-1alpha) expression. Cancer Treat Rev. 2006;32(6):407–416.
29.
YangJWangYGaoYShaoJZhangXJYaoZ. Reciprocal regulation of 17 beta-estradiol, interleukin-6 and interleukin-8 during growth and progression of epithelial ovarian cancer. Cytokine. 2009;46(3):382–391.
30.
YaoXHuangJZhongH. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014;141(2):125–139.
31.
TaylorRNLebovicDIMuellerMD. Angiogenic factors in endometriosis. Ann N Y Acad Sci. 2002;955:89–100.
32.
WuMYHoHN. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49(5):285–296.
33.
SmolenJSLandewéRBreedveldFC. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492–509.
34.
Tornero MolinaJSanmartí SalaRRodríguez ValverdeV. Update of the Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis. Reumatol Clin. 2010;6(1):23–36.
35.
YokotaSImagawaTMoriM. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371(9617):998–1006.
