• Users Online: 294
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 110-116

Indoleamine 2,3-dioxygenase in endometriosis


1 Laboratory for Reproductive Immunology, Insitute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
2 Laboratory for Reproductive Immunology, Insitute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Shanghai 200080; Laboratory for Reproductive Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Shanghai 200011; Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 230032, China

Date of Submission05-Jan-2019
Date of Web Publication9-Jul-2019

Correspondence Address:
Dr. Ming-Qing Li
Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Lane1326, Pingliang Road, Shanghai 200080
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.262391

Rights and Permissions
  Abstract 


Endometriosis (EMS) is a chronic inflammatory and estrogen-dependent gynecological disease characterized by the presence of endometrial tissue outside the uterine cavity. Although it is a benign disease, EMS is tumor-like in several aspects, which include unrestrained growth, decreased apoptosis, and aggressive invasion. EMS involves endocrine disorders and immunological factors. Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the initial and rate-limiting step of the metabolism of tryptophan. IDO is a potential candidate facilitating EMS development. Increased IDO expression in both eutopic and ectopic endometria of women with EMS is biologically important in aspects, which include regulation of endometrial stromal cell function and modulation of adjacent local immunocytes to generate a supportive microenvironment. In turn, the expression of IDO can be regulated by the complex endocrine-immune microenvironment networks in endometrial lesions. Here, we systematically review the roles of IDO in EMS to explore its pathological implications and treatment potential.

Keywords: Endometrial Stromal Cells; Endometriosis; Immunocytes; Indoleamine 2,3-Dioxygenase


How to cite this article:
Yang HL, Li MQ. Indoleamine 2,3-dioxygenase in endometriosis. Reprod Dev Med 2019;3:110-6

How to cite this URL:
Yang HL, Li MQ. Indoleamine 2,3-dioxygenase in endometriosis. Reprod Dev Med [serial online] 2019 [cited 2019 Aug 20];3:110-6. Available from: http://www.repdevmed.org/text.asp?2019/3/2/110/262391




  Introduction Top


Endometriosis (EMS) is a benign, chronic, and estrogen-dependent gynecological disease characterized by the presence of endometrial tissue outside the uterine cavity. EMS causes pelvic pain, dyspareunia, and infertility in women of reproductive age.[1] The causes of EMS are complicated and not thoroughly clear. The theory of retrograde menstruation is widely accepted. Approximately 76%–90% of women experience retrograde menstruation, whereas only 6%–10% of women develop EMS.[2] Thus, the pathogenesis of EMS cannot be determined from the endocrine perspective alone. Multiple factors participate in the development and maintenance of EMS. Women with EMS have been reported to have a biochemical, genetic, or immunological dysfunction that prevents removal of endometrial tissues from the peritoneal cavity and facilitates tissue adhesion to extrauterine structures.[3]

As a tumor-like benign disease, EMS is similar to cancer in several aspects, such as unrestrained growth, decreased apoptosis, and aggressive invasion.[4] This indicates that a microenvironment of immune tolerance is formed within ectopic lesions in patients with EMS, wherein the clearance of menstrual debris by the local immune responses is ineffective.[5] Progressive growth of ectopic tissues relies on defects of the immune system in addition to genetic and epigenetic predispositions, which allow endometrial stromal cells (ESCs) to escape apoptosis, evade immune surveillance, invade the mesothelial surface, and acquire a vascular supply.[6],[7] Data from our and others' labs have revealed that the dysfunction of immune cells in the microenvironment of the peritoneal cavity or ectopic lesions, including neutrophils, macrophages, natural killer (NK) cells, dendritic cells, T helper cells, and B cells, contributes to the pathogenesis and progression of EMS.[8],[9],[10],[11],[12]

Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the initial and rate-limiting step of the metabolism of tryptophan, an essential amino acid, in the kynurenine pathway. IDO catalyzes the metabolism of tryptophan into N-formylkynurenine and kynurenine.[13] The IDO family consists of two enzymes: IDO1 and IDO2. The IDO2 appears to be functional only in mice, not in humans.[14] IDO is expressed by a large variety of cells, including lymphocytes (dendritic cells, macrophages, and B cells), human tumor cell lines, endothelial cells, and stromal cells.[13] IDO1 has been conclusively identified as an immune modulator through tryptophan metabolism and via the generation of proapoptotic metabolites.[15],[16] For instance, IDO1 overexpression can induce the exhaustion of local tryptophan and metabolites of the kynurenine pathway, which produces immunosuppressive effects on immune cells.[17] In recent decades, IDO1 has been shown in numerous studies to produce a marked tolerance effect in organ transplantation, fetal rejection, autoimmune disorders, and cancer.[18]

IDO1 is considered a potential candidate that facilitates the development of EMS. Burney et al.[19] and Aghajanova et al.[20] described the increased IDO1 gene expression in EMS-derived eutopic endometrium and its relevance to the patients' clinical stage. Our results also revealed the expression of IDO1 in the stromal cells of the endometrium or endometriotic tissues and the pronounced expression in EMS-derived ESCs.[21]

With a deep understanding of EMS, especially from the perspective of immunity, considerable evidence supports the concept that IDO contributes to the occurrence and development of this gynecological tumor-like disease. In this review, we discuss the expression of IDO in the endometrium and endometriotic lesions and elucidate the role of IDO in EMS.


  Indoleamine 2,3-Dioxygenase in Normal Endometrium and Endometriotic Lesions Top


It has reported that IDO1 was expressed in the human female genital tract.[22] Endometrial glandular and surface epithelial cells showed increasing IDO expression during the menstrual cycle.[22] Subsequently, transcripts of IDO1 were detected in the endometrium of nonpregnant women and rhesus monkeys.[23],[24] Using Western blotting and immunohistochemistry, Jeddi-Tehrani et al.[25]obtained evidence that IDO protein is synthesized in the endometrium of cycling mice throughout the estrous cycle. IDO protein was mainly localized in the glandular and luminal epithelial cells [Table 1]. These results support the idea that IDO provides a mechanism of innate immunity to protect from ascending infections in the female reproductive tract. In addition, taking the fact that mating only occurs during the estrous phase into account, the high expression of IDO in this phase is likely to be a mechanism that induces immune tolerance of the fetus.[25] IDO1 transcript levels are likely associated with species-specific aspects of reproduction. Higher transcript levels of IDO1 in the uterus of mice were detected during estrous than during the remaining phases of the cycle.[25] In contrast, IDO1 expression in the endometrium of women was increased during the secretory phase and was barely expressed in the proliferative phase of the normal endometrium.[24] However, IDO1 protein expression was stable over the endometrial cycle in equine endometrium.[26]
Table 1: IDO1 expression in normal endometrium and endometriotic lesions

Click here to view


In the endometrium of cycling mice, IDO protein was mainly localized in the glandular and luminal epithelial cells.[25] Our previous work demonstrated that IDO1 was expressed in glandular endometrium, surface epithelial cells, and stromal cells of human endometrium.[21] Immunohistochemical detection of IDO1 in the endometria of 25 mares demonstrated that the immune-positive cell populations comprised epithelial cells, macrophages, intravascular monocytes, and neutrophils.[26] More recently, we found that NK cells in peritoneal fluid (PF) from women with or without EMS can express IDO1.[27]

Human endometriotic tissues display a high kynurenine/tryptophan ratio, compared with control tissues.[28] The ratio is also an index for IDO1 activity.[28] In the eutopic endometrium from women with EMS, microarray analysis detected higher levels of IDO1 compared with normal endometrium and was relevant to the patients' clinical stage.[19],[20] In our study, IDO1 was present in the stromal cells of endometrium or endometriotic tissues, and especially was highly expressed in EMS-derived eutopic and ectopic ESCs compared with healthy eutopic ESCs.[21] Menstrual blood-derived stromal stem cells from women with EMS (E-MenSCs) produced higher amounts of IDO1 at the gene and protein levels. Consistently, IDO1 activity in the supernatant of coculture system of E-MenSCs and peripheral blood mononuclear cells (PBMCs) was shown to be superior to that of the control.[29] However, relatively low IDO1 expression was shown specifically in equine endometriotic glands. In endometria of mares with EMS, endometriotic glands were IDO1 immune-negative or were lined by only a few weakly immune-positive epithelial cells.[26]


  Roles of Indoleamine 2,3-Dioxygenase in Endometriosis Top


Regulation of endometrial stromal cell biological behaviors

Biological behaviors of ESCs, including proliferation, autophagy, apoptosis, adhesion, and invasion, are closely associated with the pathogenesis of EMS.[30],[31],[32] Eutopic and ectopic ESCs from EMS patients expressed a higher level of matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 (COX-2) than the normal group.[21] Due to an altered production of MMPs in the eutopic endometrium from women with EMS, the retrograde endometrial tissue could be more prone to peritoneal implantation and invasion.[4] COX-2 and its derivative, prostaglandin estradiol (E2), play key roles in the origin and development of EMS through increased migration and invasiveness.[33],[34] Stimulation with IDO1 has been shown to trigger the expression of MMP-9 and COX-2 in normal and eutopic ESCs.[21] The IDO1 promoter contains motifs of transcription factor metalloendopeptidase-1, which can directly regulate the transcription of MMP genes.[35] Levo-1-methyl-tryptophan (L-1-MT), a specific inhibitor of IDO1, could reverse COX-2 upregulation triggered by lipopolysaccharide (LPS), which strongly suggests an intrinsic correlation between IDO1 and COX-2. L-1-MT could enhance decidualization in ESCsin vitro evidenced by increased prolactin (PRL) and decrease ESC survival. Moreover, L-1-MT suppressed the adhesion and invasion of ESCs.[21] Specifically, L-1-MT could abolish the increased adhesion capability of ESCs induced by LPS in Type I collagen, Type IV collagen, fibronectin, and fibrinogen. However, individual L-1-MT treatment had no effect on the initial attachment of ESCs derived from the normal control and from the eutopic group. These results indicate that inducible IDO1 expression is an important and determinant way, in which ESCs interact with the extracellular environment in vitro, but that the intrinsic IDO1 is inadequate to impact the adhesion of ESCs.[21] Consistently, we found that IDO1 overexpression in ESCs elevated cell invasiveness compared to that of normal ESCs.[36] Overexpression of IDO1 in normal ESCs elicited an increase in the phosphorylation of the c-Jun N-terminal kinase (JNK) signaling pathway. IDO1 could downregulate the expression of p53, as well as the apoptosis of ESCs through the JNK pathway. Moreover, administration of JNK inhibitor could abolish the increased invasion capability and the expressions of MMP-9 and COX-2 in ESCs induced by IDO1.[36] Therefore, the enhancement of invasion of ESCs due to MMP-9 and COX-2 secreted from IDO1-stimulated ESCs may be activated in the disease of ESCs via the JNK pathway, although further studies are needed to reinforce this suggestion. In addition, higher proliferation and invasion capacity of E-MenSCs could also be in part related to the higher IDO1 level and activity.[29]

Immune regulation

Macrophages

Macrophages are the dominant immune cells recruited to the PF from PBMCs to remove the retrograde endometrial debris. Several studies have indicated that the pelvic macrophages seem to polarize to the M2 state, which displays the alternatively activated phenotype with anti-inflammatory characteristic.[37],[38] In EMS, the inactivation of PF macrophages with respect to cytotoxicity and phagocytosis of refluxed endometrial tissue has been previously reported.[39]

The crosstalk between ESCs and macrophages has been suggested to contribute to the immune dysfunction of the endometriotic microenvironment.[12] The ectopic ESCs with higher IDO1 expression markedly inhibited the phagocytic capacity of cocultured macrophages and significantly downregulated antigen-presenting molecules, such as human leukocyte antigen-antigen D related and cluster of differentiation (CD) 11c. Conversely, ectopic ESCs promoted M2 phenotypic markers (CD163 and CD209) and intracellular M2 cytokine bias, such as low-level interleukin (IL)-23, high-level IL-10, and transforming growth factor (TGF)-β1, compared to normal ESCs. The IDO1-induced IL-33 secretion in ectopic ESCs might participate in the macrophage polarization of EMS.[40] IDO1 interference of ectopic ESCs could partly impair the effect induced by ectopic ESCs. This implicates IDO1 as a candidate molecule, but definitely not the only one, leading to the induction of macrophage tolerance during ESC-macrophage interaction, thereby participating in the impairment of peritoneal macrophage in EMS.[40] When cocultured with macrophages pretreated with IDO1-overexpressing ESCs, compared with macrophages treated with normal ESCs, the viability and proliferation of ESCs were significantly increased and apoptosis index decreased, suggesting that high levels of IDO1 expressed in the ectopic environment may induce the formation of tolerant macrophages, which, in turn, could promote ectopic ESC growth in the progression of EMS.[41]

Natural killer cells

NK cells are one of the most important cellular components of PF.[42] Cytokines change the milieu in the peritoneal cavity of patients with EMS and thus diminish the cytotoxic activity of NK cells, which is indispensable for the initiation and development of EMS.[12],[31] We have found that NK cells in PF from women with EMS highly express IDO. IDO+ NK cells present lower levels of NKp46 and NKG2D, but higher IL-10 than that of IDO NK cells. Furthermore, ESCs, especially ectopic ESCs, significantly upregulated IDO levels in NK cells, which was partly dependent on TGF-β. IDO might impair the cytotoxicity of NK cells by suppressing NKG2D and NKp46 and enhancing IL-10, resulting in the poor clearance of ectopic ESCs and finally contributing to the formation of ectopic endometrial lesions.[27]

Mast cells

Tissue-resident mast cells (MCs) are recognized as effector cells in many settings of the immune response, including immune regulation, allergy, host defense, chronic inflammation, and autoimmune diseases.[43] MCs are capable of orchestrating inflammation by modulating the recruitment and function of other immune cells, which have been reported to be involved in EMS pathogenesis.[44],[45] Diffuse infiltration of degranulated tryptase-positive MCs was observed throughout endometriotic stromal lesions and was often close to nerve fibers.[46],[47] A study recently discovered that the aryl hydrocarbon receptor (AhR), a transcription factor expressed in multiple tissues and in immune cells, modulated acute and late MC responses.[48] A number of chemicals are endogenous or physiological AhR ligands. These include tryptophan products.[49] It has been reported that endometrium-resident AhR-activated MCs, which represent an early source of IL-10, could also promote peritoneal M2 macrophage polarization into a phenotype possessing tolerogenic activity.[50] In EMS, human endometriotic tissue was reported to be rich in IDO1 and the AhR-ligand kynurenine compared with control tissue and was conducive to cytokine production, orchestrating chronic inflammation, and a population of AhR-expressing MCs that were IL-17 and IL-10 positive. High levels of kynurenine induced by increased IDO1 in endometriotic tissue possibly promoted MC activation through AhR. Moreover, endometriotic tissue was susceptible to treatment with an AhR antagonist, and ESC growth was improved in the presence of soluble factors released by MCs upon AhR activation.[28]

Regulatory T cells

IDO1 catalyzes the metabolism of tryptophan, an amino acid that is essential for T cell proliferation and differentiation.[13] IDO1 suppresses T cell responses, promotes immune tolerance, and influences the differentiation of regulatory T (Treg) cells.[51] In EMS, peritoneal Treg cells increase in number as the disease progresses. The percentage of Treg cells in the PF of EMS patients is higher than that in healthy women, and the augmentation of Treg cell percentage, especially that of TGF-β1+ Treg cells, occurs in parallel with EMS exacerbation.[52],[53] Endometriotic microenvironment is affected by changes in the proportion of Treg cells, which, in turn, plays a vital role in the maintenance of immune homeostasis to prevent potentially severe autoimmunity.[54],[55] We have found that the estrogen-IDO1-mannose receptor C, Type 2 (MRC2) axis, participated in the differentiation and function of Treg. 1-MT could inhibit Treg cell differentiation, especially that of IL-10+ Treg cells, indicating that IDO1 participates in the differentiation of Treg cells in ectopic lesions. In addition, 1-MT was involved in the suppression of Treg cells. 1-MT-pretreated ESC-educated Treg cells suppressed the proliferation of Teff (effector T) cells less effectively compared with nontreated ESC-educated Treg cells.[53]


  Regulatory Factors of Indoleamine 2,3-Dioxygenase in Endometriosis Top


IDO normally has low basal expression, but is rapidly induced by inducer of interferon (IFN)-γ alone or synergized with other proinflammatory stimuli, including tumor necrosis factor-alpha, IL-1β, and LPS in specific cell types.[56] Proinflammatory cytokines were also highly expressed in ectopic lesions and PF from women with EMS.[5],[57] Therefore, these proinflammatory cytokines may also contribute to the high level of IDO in endometriotic lesions and EMS-derived ESCs, suggesting another possible link between inflammation and the development of EMS. The striking increase in kynurenine content in endometriotic tissues compared with controls is consistent with the abundance of inflammatory cytokines observed and in other diseases in which the immune response is activated and IFN-γ is produced.[28],[58] Higher amounts of IFN-γ and monocyte chemoattractant protein-1 (MCP-1) were detected in E-MenSCs-PBMC cocultures. Higher IFN-γ production by monocytes and macrophages, which might result from higher concentration of MCP-1, should be the reason for the upregulated IDO1 expression in E-MenSCs.[29] In addition, the aberrant expression of IDO1 in eutopic endometrium could be enhanced by LPS via inflammatory mechanism and inhibited by L-1-MT.[21]

Apart from inflammation factors, several proteins that exist in ectopic lesions are secreted from ESCs, which may also regulate IDO1 production and activation. Increased IDO1 induction in the eutopic endometrium might be due to a slightly higher level of CD200, a Type I transmembrane anchored glycoprotein that is structurally similar to immunoglobulins.[59] The CD200 tolerance signaling molecule has been reported to promote Treg cells and promote IDO-production by macrophages.[60],[61] The effect of ESCs on upregulating the expression of IDO1 in macrophages was more significant than that with estrogen alone, indicating crosstalk between ESCs and macrophages related to IDO1 expression.[53] The crosstalk between ESCs and macrophages has been reported to impair the cytotoxicity of NK cells by secreting IL-10 and TGF-β in EMS.[12] In addition, ectopic ESCs led to a high level of IDO in NK cells partly by secreting a high level of TGF-β.[27] Given that TGF-β1 was reported to induce the phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in IDO and the expression of Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2 via Smad and phosphoinositol-3-kinase-dependent pathways,[62] ESC-derived TGF-β may regulate the expression of IDO in endometrial NK cells and ITIMs in IDO may inhibit NK cells-mediated cytolytic activity through SHP-2, which negatively regulates NK cell function.[27],[63]

EMS is a hormone responsive disease associated with increased levels of estrogen.[64] Increased expression of estrogen receptors (ER) α and β has been observed in ectopic tissue compared with normal and eutopic endometrium.[65] As introduced previously, estrogen-IDO1-MRC2 axis is involved in the differentiation and function of Treg cells in EMS. IDO1 expression in estrogen-conditioned ESCs and estrogen-conditioned macrophages was obviously higher than that in the control groups, suggesting that IDO1 is upregulated by estrogen in ectopic lesions. Both subunits of ER are involved in this activity, especially ERβ. Hence, estrogen promotes the differentiation of Treg cells via upregulation of IDO1 expression.[53] Engelholm et al. reported that mannose receptor C, Type 2 (MRC2), a constitutively recycling endocytic receptor belonging to the mannose receptor family,[66] was downstream to estrogen and IDO1. High levels of IDO1 might lead to the low expression of MRC2 in ectopic ESCs. After silencing MRC2 in ESCs, the expression of IDO1 increased. This result suggests that there is a negative feedback between MRC2 and IDO1.[53]


  Conclusions and Perspectives Top


EMS is more than a disease involving endocrine disorders. It also involves immunological factors. Increased IDO1 protein expression in eutopic and ectopic endometria of women with EMS has biological importance. It can directly promote the proliferation and invasion of endometrial tissue by regulating the function of ESCs [Figure 1], and can modulate adjacent immunocytes, including macrophages, NK cells, Treg cells, and MCs, to generate a supportive microenvironment [Figure 2]. These effects finally lead to the formation of endometriotic lesions and the abnormal decidualization of the endometrium.
Figure 1: Summary of biological functions of IDO1 in ESCs. IDO1 can directly promote the survival and proliferation of ESCs. IDO1 could downregulate the expression of p53 and enhance the expressions of MMP-9 and COX-2 in ESCs via JNK pathway, contributing to ESC suppression of apoptosis and promotion of invasion respectively. By downregulating PRL expression, IDO1 could also inhibit decidualization in ESCs in vitro. Moreover, IDO1 may enhance adhesion capability of ESCs by upregulating Type I collagen, Type IV collagen, fibronectin, and fibrinogen. IDO: Indoleamine 2,3-dioxygenase; ESC: Endometrial stromal cell; JNK: c-Jun N-terminal kinase; MMP-9: Matrix metalloproteinase-9; COX-2: Cyclooxygenase-2.

Click here to view
Figure 2: Schematic representation of the effects of IDO1 on immune cells and ESC function modulation of the supportive microenvironment generated by immunocytes in EMS. The crosstalk of IDO1-positive ESCs and immunocyte finally leads to the formation of endometriotic lesions and the development of EMS. (1) IDO1-induced IL-33 in ESCs might inhibit the phagocytic capacity of macrophages, significantly downregulate antigen-presenting molecules and promote M2 phenotype polarization. These tolerant macrophages could in turn promote ESC proliferation and inhibit ESC apoptosis. (2) High levels of kynurenine induced by increased IDO1 in ESC possibly promotes MC activation (IL-10 and IL-17 positive) through AhR. IL-10 derived from endometrium-resident AhR-activated MCs could promote peritoneal M2 macrophage polarization and soluble factors released by MCs upon AhR activation could promote ESC growth. (3) ESCs could significantly upregulate IDO levels in NK cells, which is partly dependent on TGF-β. IDO might impair the cytotoxicity of NK cells by suppressing NKG2D and NKp46 and enhancing IL-10, resulting in the immune escape of ESCs. (4) Downregulated MRC2 by IDO1 in ESCs could participate in the differentiation IL-10+ Treg cells, which could suppress the proliferation of Teff cells. IDO: Indoleamine 2,3-dioxygenase; ESC: Endometrial stromal cell; EMS: Endometriosis; IL: Interleukin; MCs: Mast cells; NK: Natural killer; TGF-β: Transforming growth factor-β; MRC2: Mannose receptor C, Type 2; Teff: Effector T.

Click here to view


IDO1 expression can be regulated by the endocrine condition characterized by elevated estrogen and also by immunological factors that include proinflammatory stimuli, such as IFN-γ and LPS, and anti-inflammatory cytokines that include TGF-β. In addition, several modulators in ectopic lesions, such as CD200 and MRC2, can regulate the expression of IDO1. Thus, IDO1 is involved in the information and maintenance of both the endocrine and immune microenvironment of ectopic lesions in EMS. In turn, the expression and function of IDO1 is regulated by complex endocrine-immune microenvironment networks. This information will be helpful for further investigation of the pathogenesis of EMS. However, whether increased IDO1 in eutopic and ectopic endometria of women with EMS precedes the development of disease or results afterward from development of ectopic lesions is still unclear. Further studies, especially using animal models, should be established to increase knowledge of IDO1 participation in the pathophysiology of EMS.

1-MT is also undergoing clinical Phase I and II trials concerning cancer immunotherapy.[67] The collective potential of IDO1 highlights the importance of exploring IDO1-based therapies for EMS. One example is an intrauterine device system capable of releasing 1-MT for the prevention and treatment of EMS. This and other IDO1-based therapies must not disrupt the hormonal balance. In vivo, the ESCs are exposed to autologous immune cells and complex interactions exist between ESCs and immune cells. Therefore, assessments of the local immunological status of patients with EMS are essential to guide the treatment choice. Our previous studies have implied a special immune microenvironment (coexistence of proinflammatory and anti-inflammatory factors) in the endometriotic milieu.[12] The potential value of 1-MT treatment targeting IDO1 for EMS patients with immune imbalancein vivo requires further research and exploration.

Financial support and sponsorship

This study was supported by the Major Research Program of National Natural Science Foundation of China (No. 91542108, 81471513, and 31671200), the Shanghai Rising-Star Program 16QA1400800, the Innovation-oriented Science and Technology Grant from National Population and Family Planning Commission Key Laboratory of Reproduction Regulation (CX2017-2), and the Program for Zhuoxue of Fudan University, China.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012;98:511-9. doi: 10.1016/j.fertnstert.2012.06.029.  Back to cited text no. 1
    
2.
Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol 1984;64:151-4.  Back to cited text no. 2
    
3.
Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C. Pathophysiology and immune dysfunction in endometriosis. Biomed Res Int 2015;2015:795976. doi: 10.1155/2015/795976.  Back to cited text no. 3
    
4.
Ueda M, Yamashita Y, Takehara M, Terai Y, Kumagai K, Ueki K, et al. Survivin gene expression in endometriosis. J Clin Endocrinol Metab 2002;87:3452-9. doi: 10.1210/jcem.87.7.8682.  Back to cited text no. 4
    
5.
Králíčková M, Vetvicka V. Immunological aspects of endometriosis: A review. Ann Transl Med 2015;3:153. doi: 10.3978/j.issn.2305-5839.2015.06.08.  Back to cited text no. 5
    
6.
Bulun SE. Endometriosis. N Engl J Med 2009;360:268-79. doi: 10.1056/NEJMra0804690.  Back to cited text no. 6
    
7.
Herington JL, Bruner-Tran KL, Lucas JA, Osteen KG. Immune interactions in endometriosis. Expert Rev Clin Immunol 2011;7:611-26. doi: 10.1586/eci.11.53.  Back to cited text no. 7
    
8.
Chang KK, Liu LB, Jin LP, Zhang B, Mei J, Li H, et al. IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis. Cell Death Dis 2017;8:e2666. doi: 10.1038/cddis.2017.95.  Back to cited text no. 8
    
9.
Hever A, Roth RB, Hevezi P, Marin ME, Acosta JA, Acosta H, et al. Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. Proc Natl Acad Sci U S A 2007;104:12451-6. doi: 10.1073/pnas.0703451104.  Back to cited text no. 9
    
10.
Kwak JY, Park SW, Kim KH, Na YJ, Lee KS. Modulation of neutrophil apoptosis by plasma and peritoneal fluid from patients with advanced endometriosis. Hum Reprod 2002;17:595-600. doi: 10.1093/humrep/17.3.595.  Back to cited text no. 10
    
11.
Schulke L, Berbic M, Manconi F, Tokushige N, Markham R, Fraser IS. Dendritic cell populations in the eutopic and ectopic endometrium of women with endometriosis. Hum Reprod 2009;24:1695-703. doi: 10.1093/humrep/dep071.  Back to cited text no. 11
    
12.
Yang HL, Zhou WJ, Chang KK, Mei J, Huang LQ, Wang MY, et al. The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β. Reproduction 2017;154:815-25. doi: 10.1530/REP-17-0342.  Back to cited text no. 12
    
13.
Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 1991;5:2516-22.  Back to cited text no. 13
    
14.
Lob S, Konigsrainer A, Schafer R, Rammensee HG, Opelz G, Terness P. Levo-but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells. Blood 2008;111:2152-4. doi: 10.1182/blood-2007-10-116111.  Back to cited text no. 14
    
15.
Palafox D, Llorente L, Alberú J, Torres-Machorro A, Camorlinga N, Rodríguez C, et al. The role of indoleamine 2,3 dioxygenase in the induction of immune tolerance in organ transplantation. Transplant Rev (Orlando) 2010;24:160-5. doi: 10.1016/j.trre.2010.04.003.  Back to cited text no. 15
    
16.
Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase: Is it an immune suppressor? Cancer J 2010;16:354-9. doi: 10.1097/PPO.0b013e3181eb3343.  Back to cited text no. 16
    
17.
King NJ, Thomas SR. Molecules in focus: Indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol 2007;39:2167-72. doi: 10.1016/j.biocel.2007.01.004.  Back to cited text no. 17
    
18.
Mándi Y, Vécsei L. The kynurenine system and immunoregulation. J Neural Transm (Vienna) 2012;119:197-209. doi: 10.1007/s00702-011-0681-y.  Back to cited text no. 18
    
19.
Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 2007;148:3814-26. doi: 10.1210/en.2006-1692.  Back to cited text no. 19
    
20.
Aghajanova L, Giudice LC. Molecular evidence for differences in endometrium in severe versus mild endometriosis. Reprod Sci 2011;18:229-51. doi: 10.1177/1933719110386241.  Back to cited text no. 20
    
21.
Mei J, Jin LP, Ding D, Li MQ, Li DJ, Zhu XY. Inhibition of IDO1 suppresses cyclooxygenase-2 and matrix metalloproteinase-9 expression and decreases proliferation, adhesion and invasion of endometrial stromal cells. Mol Hum Reprod 2012;18:467-76. doi: 10.1093/molehr/gas021.  Back to cited text no. 21
    
22.
Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, et al. Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. Mol Hum Reprod 2002;8:385-91. doi: 10.1093/molehr/8.4.385.  Back to cited text no. 22
    
23.
Drenzek JG, Breburda EE, Burleigh DW, Bondarenko GI, Grendell RL, Golos TG. Expression of indoleamine 2,3-dioxygenase in the rhesus monkey and common marmoset. J Reprod Immunol 2008;78:125-33. doi: 10.1016/j.jri.2008.03.005.  Back to cited text no. 23
    
24.
Lobo SC, Huang ST, Germeyer A, Dosiou C, Vo KC, Tulac S, et al. The immune environment in human endometrium during the window of implantation. Am J Reprod Immunol 2004;52:244-51. doi: 10.1111/j.1600-0897.2004.00217.x.  Back to cited text no. 24
    
25.
Jeddi-Tehrani M, Abbasi N, Dokouhaki P, Ghasemi J, Rezania S, Ostadkarampour M, et al. Indoleamine 2,3-dioxygenase is expressed in the endometrium of cycling mice throughout the oestrous cycle. J Reprod Immunol 2009;80:41-8. doi: 10.1016/j.jri.2009.02.003.  Back to cited text no. 25
    
26.
Schöniger S, Gräfe H, Richter F, Schoon HA. Expression of indoleamine 2,3-dioxygenase 1 as transcript and protein in the healthy and diseased equine endometrium. Res Vet Sci 2018;118:278-87. doi: 10.1016/j.rvsc.2018.03.001.  Back to cited text no. 26
    
27.
Liu XT, Sun HT, Zhang ZF, Shi RX, Liu LB, Yu JJ, et al. Indoleamine 2,3-dioxygenase suppresses the cytotoxicity of 1 NK cells in response to ectopic endometrial stromal cells in endometriosis. Reproduction 2018;156:397-404. doi: 10.1530/REP-18-0112.  Back to cited text no. 27
    
28.
Mariuzzi L, Domenis R, Orsaria M, Marzinotto S, Londero AP, Bulfoni M, et al. Functional expression of aryl hydrocarbon receptor on mast cells populating human endometriotic tissues. Lab Invest 2016;96:959-71. doi: 10.1038/labinvest.2016.74.  Back to cited text no. 28
    
29.
Nikoo S, Ebtekar M, Jeddi-Tehrani M, Shervin A, Bozorgmehr M, Vafaei S, et al. Menstrual blood-derived stromal stem cells from women with and without endometriosis reveal different phenotypic and functional characteristics. Mol Hum Reprod 2014;20:905-18. doi: 10.1093/molehr/gau044.  Back to cited text no. 29
    
30.
Yang HL, Chang KK, Mei J, Zhou WJ, Liu LB, Yao L, et al. Estrogen restricts the apoptosis of endometrial stromal cells by promoting TSLP secretion. Mol Med Rep 2018;18:4410-6. doi: 10.3892/mmr.2018.9428.  Back to cited text no. 30
    
31.
Yu JJ, Sun HT, Zhang ZF, Shi RX, Liu LB, Shang WQ, et al. IL15 promotes growth and invasion of endometrial stromal cells and inhibits killing activity of NK cells in endometriosis. Reproduction 2016;152:151-60. doi: 10.1530/REP-16-0089.  Back to cited text no. 31
    
32.
Zhang B, Zhou WJ, Gu CJ, Wu K, Yang HL, Mei J, et al. The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity. Cell Death Dis 2018;9:574. doi: 10.1038/s41419-018-0581-2.  Back to cited text no. 32
    
33.
Banu SK, Lee J, Speights VO Jr., Starzinski-Powitz A, Arosh JA. Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms. Endocrinology 2008;149:1180-9. doi: 10.1210/en.2007-1168.  Back to cited text no. 33
    
34.
Collette T, Maheux R, Mailloux J, Akoum A. Increased expression of matrix metalloproteinase-9 in the eutopic endometrial tissue of women with endometriosis. Hum Reprod 2006;21:3059-67. doi: 10.1093/humrep/del297.  Back to cited text no. 34
    
35.
Labbé S, Larouche L, Mailhot D, Séguin C. Purification of mouse MEP-1, a nuclear protein which binds to the metal regulatory elements of genes encoding metallothionein. Nucleic Acids Res 1993;21:1549-54. doi: 10.1093/nar/21.7.1549.  Back to cited text no. 35
    
36.
Mei J, Li MQ, Ding D, Li DJ, Jin LP, Hu WG,et al. Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway. Int J Clin Exp Pathol 2013;6:431-44.  Back to cited text no. 36
    
37.
Bacci M, Capobianco A, Monno A, Cottone L, Di Puppo F, Camisa B, et al. Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. Am J Pathol 2009;175:547-56. doi: 10.2353/ajpath.2009.081011.  Back to cited text no. 37
    
38.
Itoh F, Komohara Y, Takaishi K, Honda R, Tashiro H, Kyo S, et al. Possible involvement of signal transducer and activator of transcription-3 in cell-cell interactions of peritoneal macrophages and endometrial stromal cells in human endometriosis. Fertil Steril 2013;99:1705-13. doi: 10.1016/j.fertnstert.2013.01.133.  Back to cited text no. 38
    
39.
Chuang PC, Lin YJ, Wu MH, Wing LY, Shoji Y, Tsai SJ. Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. Am J Pathol 2010;176:850-60. doi: 10.2353/ajpath.2010.090551.  Back to cited text no. 39
    
40.
Mei J, Xie XX, Li MQ, Wei CY, Jin LP, Li DJ,et al. Indoleamine 2,3-dioxygenase-1 (IDO1) in human endometrial stromal cells induces macrophage tolerance through interleukin-33 in the progression of endometriosis. Int J Clin Exp Pathol 2014;7:2743-57.  Back to cited text no. 40
    
41.
Mei J, Chang KK, Sun HX. Immunosuppressive macrophages induced by IDO1 promote the growth of endometrial stromal cells in endometriosis. Mol Med Rep 2017;15:2255-60. doi: 10.3892/mmr.2017.6242.  Back to cited text no. 41
    
42.
Gazvani R, Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction 2002;123:217-26.  Back to cited text no. 42
    
43.
Rao KN, Brown MA. Mast cells: Multifaceted immune cells with diverse roles in health and disease. Ann N Y Acad Sci 2008;1143:83-104. doi: 10.1196/annals.1443.023.  Back to cited text no. 43
    
44.
Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: Negative, as well as positive, regulators of immunity. Nat Rev Immunol 2008;8:478-86. doi: 10.1038/nri2327.  Back to cited text no. 44
    
45.
Kirchhoff D, Kaulfuss S, Fuhrmann U, Maurer M, Zollner TM. Mast cells in endometriosis: Guilty or innocent bystanders? Expert Opin Ther Targets 2012;16:237-41. doi: 10.1517/14728222.2012.661415.  Back to cited text no. 45
    
46.
Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noël JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 2006;86:1336-43. doi: 10.1016/j.fertnstert.2006.03.057.  Back to cited text no. 46
    
47.
Sugamata M, Ihara T, Uchiide I. Increase of activated mast cells in human endometriosis. Am J Reprod Immunol 2005;53:120-5. doi: 10.1111/j.1600-0897.2005.00254.x.  Back to cited text no. 47
    
48.
Sibilano R, Frossi B, Calvaruso M, Danelli L, Betto E, Dall'Agnese A, et al. The aryl hydrocarbon receptor modulates acute and late mast cell responses. J Immunol 2012;189:120-7. doi: 10.4049/jimmunol.1200009.  Back to cited text no. 48
    
49.
Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 2003;43:309-34. doi: 10.1146/annurev.pharmtox.43.100901.135828.  Back to cited text no. 49
    
50.
Sica A, Mantovani A. Macrophage plasticity and polarization:In vivo veritas. J Clin Invest 2012;122:787-95. doi: 10.1172/JCI59643.  Back to cited text no. 50
    
51.
Puccetti P, Grohmann U. IDO and regulatory T cells: A role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol 2007;7:817-23. doi: 10.1038/nri2163.  Back to cited text no. 51
    
52.
Olkowska-Truchanowicz J, Bocian K, Maksym RB, Białoszewska A, Włodarczyk D, Baranowski W, et al. CD4+ CD25+ FOXP3+ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. Hum Reprod 2013;28:119-24. doi: 10.1093/humrep/des346.  Back to cited text no. 52
    
53.
Wei C, Mei J, Tang L, Liu Y, Li D, Li M, et al. 1-methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis. Cell Death Dis 2016;7:e2489. doi: 10.1038/cddis.2016.375.  Back to cited text no. 53
    
54.
Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 2011;12:304-11. doi: 10.1038/ni.2006.  Back to cited text no. 54
    
55.
Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol 2014;14:154-65. doi: 10.1038/nri3605.  Back to cited text no. 55
    
56.
Fujigaki S, Saito K, Sekikawa K, Tone S, Takikawa O, Fujii H, et al. Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanism. Eur J Immunol 2001;31:2313-8. doi: 10.1002/1521-4141(200108)31:8<2313::AID-IMMU2313>3.0.CO;2-S.  Back to cited text no. 56
    
57.
Ritter U, Moll H. Monocyte chemotactic protein-1 stimulates the killing of leishmania major by human monocytes, acts synergistically with IFN-gamma and is antagonized by IL-4. Eur J Immunol 2000;30:3111-20. doi: 10.1002/1521-4141(200011)30:11<3111::AID-IMMU3111>3.0.CO;2-O.  Back to cited text no. 57
    
58.
Chen Y, Guillemin GJ. Kynurenine pathway metabolites in humans: Disease and healthy states. Int J Tryptophan Res 2009;2:1-9.  Back to cited text no. 58
    
59.
Clark DA, Dmetrichuk JM, Dhesy-Thind S, Crowther MA, Arredondo JL. Soluble CD200 in secretory phase endometriosis endometrial venules may explain endometriosis pathophysiology and provide a novel treatment target. J Reprod Immunol 2018;129:59-67. doi: 10.1016/j.jri.2018.05.006.  Back to cited text no. 59
    
60.
Clark DA. The importance of being a regulatory T cell in pregnancy. J Reprod Immunol 2016;116:60-9. doi: 10.1016/j.jri.2016.04.288.  Back to cited text no. 60
    
61.
Clark DA. Mouse is the new woman? Translational research in reproductive immunology. Semin Immunopathol 2016;38:651-68. doi: 10.1007/s00281-015-0553-x.  Back to cited text no. 61
    
62.
Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol 2011;12:870-8. doi: 10.1038/ni.2077.  Back to cited text no. 62
    
63.
Purdy AK, Campbell KS. SHP-2 expression negatively regulates NK cell function. J Immunol 2009;183:7234-43. doi: 10.4049/jimmunol.0900088.  Back to cited text no. 63
    
64.
Rizner TL. Estrogen metabolism and action in endometriosis. Mol Cell Endocrinol 2009;307:8-18. doi: 10.1016/j.mce.2009.03.022.  Back to cited text no. 64
    
65.
Pellegrini C, Gori I, Achtari C, Hornung D, Chardonnens E, Wunder D, et al. The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis. Fertil Steril 2012;98:1200-8. doi: 10.1016/j.fertnstert.2012.06.056.  Back to cited text no. 65
    
66.
Engelholm LH, Ingvarsen S, Jürgensen HJ, Hillig T, Madsen DH, Nielsen BS,et al. The collagen receptor uPARAP/Endo180. Front Biosci (Landmark Ed) 2009;14:2103-14.  Back to cited text no. 66
    
67.
Barth H, Raghuraman S. Persistent infectious diseases say – IDO. Role of indoleamine-2,3-dioxygenase in disease pathogenesis and implications for therapy. Crit Rev Microbiol 2014;40:360-8. doi: 10.3109/1040841X.2012.742037.  Back to cited text no. 67
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Indoleamine 2,3-...
Roles of Indolea...
Regulatory Facto...
Conclusions and ...
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed51    
    Printed4    
    Emailed0    
    PDF Downloaded14    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]