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Int J Clin Exp Pathol 2013;6(10):2011-2020
Original Article
IL-22 in the endometriotic milieu promotes the proliferation of endometrial stromal cells
via stimulating the secretion of CCL2 and IL-8
Yan Guo, Ying Chen, Li-Bing Liu, Kai-Kai Chang, Hui Li, Ming-Qing Li, Jun Shao
Department of Pathology, Yixing Second People’s Hospital, Yixing, Jiangsu Province 214221, People’s Republic of China; Laboratory for
Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011,
People’s Republic of China; Department of Obstetrics and Gynecology, The Fourth Hospital of Soochow University, Wuxi 214062, People’s
Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, People’s Republic of
China. Equal contributors.
Received August 3, 2013; Accepted August 21, 2013; Epub September 15, 2013; Published October 1, 2013
Abstract: Interleukin-22 (IL-22) is a member of the IL-10 cytokine family and plays critical roles in inflammation, immune surveillance, and
tissue homeostasis. However, whether IL-22 regulates the growth of endometrial stromal cells (ESCs), and participates in the pathogenesis of
endometriosis remain unclear. In this study, we found that the expression of IL-22 and it receptors (IL-22R1 and IL-10R2) in eutopic
endometrium and ectopic lesion of women with endometriosis was higher than that from healthy control. Recombinant human IL-22 (rhIL-22)
stimulated the proliferation of ESCs in a dosage-dependent manner. On the contrary, anti-human IL-22 neutralizing antibody inhibited the
proliferation of ESCs in vitro. The stimulatory effect of IL-22 on the proliferation of ESCs could be reversed by inhibitor of STAT5, ERK1/2 or AKT
signal pathway. However, blocking STAT3, JNK or P38 signal pathway had no these effects. By Enzyme-linked immunosorbent assay (ELISA)
and flow cytometry assay, we demonstrated the rhIL-22 not only stimulate the secretion of CCL2 and IL-8, but also significantly up-regulate the
expression of IL-8 receptor CXCR1 on ESCs. Meanwhile, STAT5, ERK1/2 and or AKT signal inhibitors could abrogate the increase of CCL2, IL-
8 and CXCR1 levels induced by rhIL-22. However, rhIL-22 had not similar influence on CCL2 receptor CCR2. Our current results suggested
that the higher level of IL-22 and it receptors in eutopic endometrium may stimulate the expression of CCL2, IL-8/CXCR1, and further promote
the growth of ESCs possibly through activating STAT5, MAPK/ERK1/2 and or AKT signal pathways, which may be involved in the occurrence and
development of endometriosis. (IJCEP1308008).
Keywords: IL-22, endometrial stromal cells, proliferation, CCL2, IL-8, endometriosis
Address correspondence to: Jun Shao, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics & Gynecology, Fudan
University Shanghai Medical College, Shanghai 200011, China. E-mail: junshao700523@gmail.com
Original Article
IL-22 in the endometriotic milieu promotes the proliferation of endometrial stromal cells
via stimulating the secretion of CCL2 and IL-8
Yan Guo, Ying Chen, Li-Bing Liu, Kai-Kai Chang, Hui Li, Ming-Qing Li, Jun Shao
Department of Pathology, Yixing Second People’s Hospital, Yixing, Jiangsu Province 214221, People’s Republic of China; Laboratory for
Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011,
People’s Republic of China; Department of Obstetrics and Gynecology, The Fourth Hospital of Soochow University, Wuxi 214062, People’s
Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, People’s Republic of
China. Equal contributors.
Received August 3, 2013; Accepted August 21, 2013; Epub September 15, 2013; Published October 1, 2013
Abstract: Interleukin-22 (IL-22) is a member of the IL-10 cytokine family and plays critical roles in inflammation, immune surveillance, and
tissue homeostasis. However, whether IL-22 regulates the growth of endometrial stromal cells (ESCs), and participates in the pathogenesis of
endometriosis remain unclear. In this study, we found that the expression of IL-22 and it receptors (IL-22R1 and IL-10R2) in eutopic
endometrium and ectopic lesion of women with endometriosis was higher than that from healthy control. Recombinant human IL-22 (rhIL-22)
stimulated the proliferation of ESCs in a dosage-dependent manner. On the contrary, anti-human IL-22 neutralizing antibody inhibited the
proliferation of ESCs in vitro. The stimulatory effect of IL-22 on the proliferation of ESCs could be reversed by inhibitor of STAT5, ERK1/2 or AKT
signal pathway. However, blocking STAT3, JNK or P38 signal pathway had no these effects. By Enzyme-linked immunosorbent assay (ELISA)
and flow cytometry assay, we demonstrated the rhIL-22 not only stimulate the secretion of CCL2 and IL-8, but also significantly up-regulate the
expression of IL-8 receptor CXCR1 on ESCs. Meanwhile, STAT5, ERK1/2 and or AKT signal inhibitors could abrogate the increase of CCL2, IL-
8 and CXCR1 levels induced by rhIL-22. However, rhIL-22 had not similar influence on CCL2 receptor CCR2. Our current results suggested
that the higher level of IL-22 and it receptors in eutopic endometrium may stimulate the expression of CCL2, IL-8/CXCR1, and further promote
the growth of ESCs possibly through activating STAT5, MAPK/ERK1/2 and or AKT signal pathways, which may be involved in the occurrence and
development of endometriosis. (IJCEP1308008).
Keywords: IL-22, endometrial stromal cells, proliferation, CCL2, IL-8, endometriosis
Address correspondence to: Jun Shao, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics & Gynecology, Fudan
University Shanghai Medical College, Shanghai 200011, China. E-mail: junshao700523@gmail.com
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