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Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway.

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.

SUBMITTER: Mei J

PROVIDER: S-EPMC3563200 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway.

Mei Jie J Li Ming-Qing MQ Ding Ding D Li Da-Jin DJ Jin Li-Ping LP Hu Wei-Guo WG Zhu Xiao-Yong XY

International journal of clinical and experimental pathology 20130215 3

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 ...[more]

PMID: 23411497

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Project description:In the peritoneal fluid, macrophages and their secretory cytokines are essential for endometriosis, but the factors that favor their involvement in the endometriosis-associated inflammatory response are still elusive. Given the anomalous expression of indoleamine 2,3-dioxygenase-1 (IDO1) in endometrial stromal cells (ESCs) and its potentially important roles in immune modulation, we aimed to determine the effects of IDO1 in ESCs on macrophages and the mechanism of those effects. Normal ESCs and ectopic ESCs transfected with the SD11-IDO1 shRNA (short hairpin RNA) or vector-only plasmid SD11 were subsequently co-cultured with peripheral blood (PB)-derived monocytes (PBMC)-driven macrophages directly and indirectly. Cytokine production was determined by analyzing the supernatant of the co-culture unit by enzyme-linked immunosorbent assay (ELISA). The phenotypes and the phagocytic ability of the macrophages were determined by flow cytometry. Compared to normal ESCs, the PBMC-driven macrophages co-cultured with ectopic ESCs displayed lower phagocytic ability. Additionally, macrophages co-cultured with ectopic ESCs exhibited higher levels of CD163 and CD209 and lower levels of HLA-DR and CD11c. Moreover, both the intracellular expression and extracellular secretion of interleukin-10 (IL-10) and transforming growth factor-?1 (TGF-?1) were significantly increased, while that of IL-12p70 was decreased in macrophages after being co-cultured with ectopic ESCs. However, there was no significant difference in macrophage phagocytic ability, immunophenotype or cytokine secretion between the direct and indirect co-culture units. Reversely, SD11-IDO1 shRNA transfection of ectopic ESCs could abrogate the decreased phagocytic ability and alternative activation of macrophages in ectopic ESC-macrophage co-culture unit, suggesting that higher IDO1 in ectopic ESCs was indispensable for the induction of macrophage tolerance. Furthermore, the decrease in phagocytic macrophages and alternatively activated macrophages induced by IDO1 in ectopic ESCs was reversed by the addition of an IL-33 inhibitor, that is, soluble ST2 (sST2). Therefore, through the activation of IL-33, the increased expression of IDO1 in ectopic ESCs contributed to the truncated phagocytic ability of macrophages in endometriosis.

Dataset Information

Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway.

Publications

Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway.

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