Endometriosis is an estrogen (ER)-dependent gynecological disease caused by the growth of endometrial tissue at extrauterine sites. Current endocrine therapies address the estrogenic aspect of disease and offer some relief from pain but are associated with significant side effects. Immune dysfunction is also widely believed to be an underlying contributor to the pathogenesis of this disease. This study evaluated an inhibitor of c-Jun N-terminal kinase, bentamapimod (AS602801), which interrupts immune pathways, in 2 rodent endometriosis models. Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS602801 caused 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS602801 alone or MPA + AS602801 suppressed MMP-3 production. In an autologous rat endometriosis model, AS602801 caused 48% regression of lesions compared to GnRH antagonist Antide (84%). AS602801 reduced inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns were unaffected. Furthermore, AS602801 enhanced natural killer cell activity, without apparent negative effects on uterus. These results indicate that bentamapimod induced regression of endometriotic lesions in endometriosis rodent animal models without suppressing ER action. c-Jun N-terminal kinase inhibition mediated a comprehensive reduction in cytokine secretion and moreover was able to overcome PR resistance.
KyamaCMDebrockSMwendaJMD’HoogheTM. Potential involvement of the immune system in the development of endometriosis. Reprod Biol Endocrinol. 2003;1:123.
2.
LebovicDIMuellerMDTaylorRN. Immunobiology of endometriosis. Fertil Steril. 2001;75(1):1–10.
3.
SenturkLMAriciA. Immunology of endometriosis. J Reprod Immunol. 1999;43(1):67–83.
4.
BulunSEChengYHYinP. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248(1-2):94–103.
5.
HastingsJMFazleabasAT. A baboon model for endometriosis: implications for fertility. Reprod Biol Endocrinol. 2006;4(suppl 1):S7.
6.
GaetjeRKotzianSHerrmannGBaumannRStarzinski-PowitzA. Nonmalignant epithelial cells, potentially invasive in human endometriosis, lack the tumor suppressor molecule E-cadherin. Am J Pathol. 1997;150(2):461–467.
7.
MatsuzakiSDarchaC. Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. Hum Reprod. 2012;27(3):712–721.
8.
Al-SabbaghMLamEWBrosensJJ. Mechanisms of endometrial progesterone resistance. Mol Cell Endocrinol. 2012;358(2):208–215.
9.
DunselmanGAVermeulenNBeckerC. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400–412.
10.
StreuliIde ZieglerDSantulliP. An update on the pharmacological management of endometriosis. Expert Opin Pharmacother. 2013;14(3):291–305.
11.
EfstathiouJASampsonDALevineZ. Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model. Fertil Steril. 2005;83(1):171–181.
12.
BulunSE. Endometriosis. N Engl J Med. 2009;360(3):268–279.
13.
HeringtonJLBruner-TranKLLucasJAOsteenKG. Immune interactions in endometriosis. Expert Rev Clin Immunol. 2011;7(5):611–626.
14.
BarczEMilewskiLDziunyczPKaminskiPPloskiRMalejczykJ. Peritoneal cytokines and adhesion formation in endometriosis: an inverse association with vascular endothelial growth factor concentration. Fertil Steril. 2012;97(6):1380–1386. e1381.
15.
BraunDPDingJDmowskiWP. Peritoneal fluid-mediated enhancement of eutopic and ectopic endometrial cell proliferation is dependent on tumor necrosis factor-alpha in women with endometriosis. Fertil Steril. 2002;78(4):727–732.
16.
KeenanJAChenTTChadwellNLTorryDSCaudleMR. IL-1 beta, TNF-alpha, and IL-2 in peritoneal fluid and macrophage-conditioned media of women with endometriosis. Am J Reprod Immunol. 1995;34(6):381–385.
17.
D’HoogheTMNugentNPCuneoS. Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drug-controlled study. Biol Reprod. 2006;74(1):131–136.
18.
BarrierBFBatesGWLelandMMLeachDARobinsonRDPropstAM. Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril. 2004;81(suppl 1):775–779.
19.
FalconerHMwendaJMChaiDC. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod. 2006;21(7):1856–1862.
20.
Peyrin-BirouletLDeltenrePde SurayNBrancheJSandbornWJColombelJF. Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol. 2008;6(6):644–653.
21.
YoshinoOOsugaYHirotaY. Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am J Reprod Immunol. 2004;52(5):306–311.
22.
GaillardPJeanclaude-EtterIArdissoneV. Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J Med Chem. 2005;48(14):4596–4607.
23.
FerrandiCRichardFTavanoP. Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers. Mult Scler. 2011;17(1):43–56.
24.
KaoLCGermeyerATulacS. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144(7):2870–2881.
25.
MatsuzakiSCanisMPoulyJLBotchorishviliRDechelottePJMageG. Differential expression of genes in eutopic and ectopic endometrium from patients with ovarian endometriosis. Fertil Steril. 2006;86(3):548–553.
26.
MatsuzakiSCanisMVaurs-BarriereCBoespflug-TanguyODastugueBMageG. DNA microarray analysis of gene expression in eutopic endometrium from patients with deep endometriosis using laser capture microdissection. Fertil Steril. 2005;84(suppl 2):1180–1190.
27.
WuYKajdacsy-BallaAStrawnE. Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology. 2006;147(1):232–246.
28.
ShazandKBabanSPriveC. FOXO1 and c-jun transcription factors mRNA are modulated in endometriosis. Mol Hum Reprod. 2004;10(12):871–877.
29.
UzYHMurkWBozkurtIKizilayGAriciAKayisliUA. Increased c-Jun N-terminal kinase activation in human endometriotic endothelial cells. Histochem Cell Biol. 2011;135(1):83–91.
30.
GrundEMKaganDTranCA. Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. Mol Pharmacol. 2008;73(5):1394–1404.
31.
MillerMAMeyerASBesteMT. ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling. Proc Natl Acad Sci U S A. 2013;110(22):E2074–E2083.
32.
CarboniSBoschertUGaillardPGottelandJPGillonJYVittePA. AS601245, a c-Jun NH2-terminal kinase (JNK) inhibitor, reduces axon/dendrite damage and cognitive deficits after global cerebral ischaemia in gerbils. Br J Pharmacol. 2008;153(1):157–163.
33.
TokushigeNMarkhamRRussellPFraserIS. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Fertil Steril. 2007;88(4):795–803.
34.
BrunerKLEisenbergEGorsteinFOsteenKG. Progesterone and transforming growth factor-beta coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis. Steroids. 1999;64(9):648–653.
35.
Bruner-TranKLZhangZEisenbergEWinnekerRCOsteenKG. Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget. J Clin Endocrinol Metab. 2006;91(4):1554–1560.
36.
D’AntonioMMartelliFPeanoSPapoianRBorrelliF. Ability of recombinant human TNF binding protein-1 (r-hTBP-1) to inhibit the development of experimentally-induced endometriosis in rats. J Reprod Immunol. 2000;48(2):81–98.
37.
BesteMTPfaffle-DoyleNPrenticeEA. Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation. Sci Transl Med. 2014;6(222):222ra216.
38.
KobayashiHHigashiuraYShigetomiHKajiharaH. Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation (Review). Mol Med Rep. 2014;9(1):9–15.
39.
BiancoBAndreGMVilarinoFL. The possible role of genetic variants in autoimmune-related genes in the development of endometriosis. Hum Immunol. 2012;73(3):306–315.
40.
KoninckxPRCraessaertsMTimmermanDCornillieFKennedyS. Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Reprod. 2008;23(9):2017–2023.
41.
PappK. Clinical development of onercept, a tumor necrosis factor binding protein, in psoriasis. Curr Med Res Opin. 2010;26(10):2287–2300.
42.
BulunSEChengYHPavoneME. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):36–43.
43.
BulunSEChengYHPavoneME. 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):44–50.
44.
GallinelliAChiossiGGiannellaLMarsellaTGenazzaniADVolpeA. Different concentrations of interleukins in the peritoneal fluid of women with endometriosis: relationships with lymphocyte subsets. Gynecol Endocrinol. 2004;18(3):144–151.
45.
HaradaTIwabeTTerakawaN. Role of cytokines in endometriosis. Fertil Steril. 2001;76(1):1–10.
46.
Mier-CabreraJJimenez-ZamudioLGarcia-LatorreECruz-OrozcoOHernandez-GuerreroC. Quantitative and qualitative peritoneal immune profiles, T-cell apoptosis and oxidative stress-associated characteristics in women with minimal and mild endometriosis. BJOG. 2011;118(1):6–16.
47.
AltanZMDenisDKaganDGrundEMPalmerSSNatarajaSG. A long-acting tumor necrosis factor alpha-binding protein demonstrates activity in both in vitro and in vivo models of endometriosis. J Pharmacol Exp Ther. 2010;334(2):460–466.
48.
UmesakiNTanakaTMiyamaMMizunoKKawamuraNOgitaS. Increased natural killer cell activities in patients treated with gonadotropin releasing hormone agonist. Gynecol Obstet Invest. 1999;48(1):66–68.
49.
TanakaESendoFKawagoeSHiroiM. Decreased natural killer cell activity in women with endometriosis. Gynecol Obstet Invest. 1992;34(1):27–30.
50.
QuarantaMGPorporaMGMattioliB. Impaired NK-cell-mediated cytotoxic activity and cytokine production in patients with endometriosis: a possible role for PCBs and DDE. Life Sci. 2006;79(5):491–498.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
