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Int J Clin Exp Pathol 2013;6(3):431-444

Original Article
Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and inva-siveness of
endometrial stromal cells via the activation of JNK signal-ing pathway

Jie Mei, Ming-Qing Li, Ding Ding, Da-Jin Li, Li-Ping Jin, Wei-Guo Hu, Xiao-Yong Zhu

Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics & Gynecology, Shanghai Medical School, Fudan University,
Shanghai, 200011, China; The Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
Received December 12, 2012; Accepted January 27, 2013; Epub February 15, 2013; Published March 1, 2013

Abstract: Evidence for an immunosuppressive function of indoleamine 2,3-dioxygenase (IDO) has been accumulating. However, the unusual
distribution of IDO1 in gynecologic cancer cells suggests that modulating immunity may not its only function. To clarify the physiological
importance of IDO1 in endometriosis, a tumor-like benign disease, we have investigated the potential mechanism by which IDO1 modulated
endometrial stromal cells (ESCs) proliferation and invasion. ESCs were obtained from 16 control women (normal) and 14 patients with ovarian
endometrioma, then the normal ESCs were treated with plasmid pEGFP-N1-IDO1 or SD11-IDO1 short hairpin RNA (shRNA) alone, or in
combination with c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and subjected to cell viability, proliferation, apoptosis assay and Matrigel
invasion assay. IDO1 mRNA expression was evaluated by quantitative real-time reverse transcription-polymerase chain reaction (real-time
PCR), and protein levels of IDO1, survivin, protein 53 (p53), matrix metalloproteinase (MMP)-2, MMP-9, tissue-inhibitor of metalloproteinase-1
(TIMP-1) and cyclooxygenase-2 (COX-2) in IDO1-overexpressing and IDO1-deficiency ESCs were analyzed by in-cell Western. We found that
IDO1 expression was higher in endometriosis-derived eutopic and ectopic ESCs, compared with endometriosis-free normal ESCs. As a result,
IDO1-overexpression in ESCs was markedly linked to reduction of apoptosis and p53 expression, and upregulation of survival, proliferation,
invasion, as well as expression of MMP-9, COX-2 expression, rather than expression of survivin, MMP-2 and TIMP-1. Reversely, JNK blockage
could abrogate these alterations of ESCs in IDO1-overexpressing milieu, suggesting that JNK signaling pathway was indispensable for ESCs
survival, proliferation and invasion enhanced by IDO1, which may contribute to the pathophysiology of endometriosis. (IJCEP1212018).

Keywords: Endometriosis, indoleamine 2,3-dioxygenase, endometrial stromal cells

Address correspondence to: Dr. Xiao-Yong Zhu and Wei-Guo Hu, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics
& Gynecology, Shanghai Medical School, Fudan University, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases,
Fang Xie Road 419, Shanghai, 200011, China. Tel: 86-21-63455050; Fax: 86-21-63457331; E-mail: zhuxiaoyong@fudan.edu.cn (X.-Y.Z.);
dochwg@gmail.com (W.-G.H)