Recruitment of CCR6-expressing Th17 cells by CCL 20 secreted from IL-1 beta-, TNF-alpha-, and IL-17A-stimulated endometriotic stromal cells.
In a novel paradigm of T cell differentiation, type 17 T helper (Th17) cells may play a significant role in endometriosis, a chronic inflammatory disease. However, the mechanism regulating the accumulation of Th17 cells in endometriotic tissues remains unknown. We hypothesized that Th17 cells migrate to endometriotic tissues through an interaction of the chemokine CC chemokine ligand (CCL)20 and its receptor CCR6. Using endometriotic tissues from women with endometriosis, we demonstrated, by flow cytometry, that Th17 cells in endometriotic tissues express CC chemokine receptor (CCR)6. Immunohistochemistry also revealed that CCL20 was expressed in the epithelial cells and stromal cells beneath the epithelium of endometriotic tissues. CCR6+ cells were small and round and scattered in the stroma in which abundant CCL20+ cells were detected. CCL20 caused selective migration of Th17 cells in the peripheral blood in a migration assay. IL-1β, TNF-α, and IL-17A increased the secretion of CCL20 in cultured endometriotic stromal cells. Inhibitors of p38- and p42/44-MAPKs, and stress-activated protein kinase/c-Jun kinase suppressed the secretion of CCL20 increased by IL-1β, TNF-α, and IL-17A. This suggests that the CCL20/CCR6 system is involved in the migration of Th17 cells to endometriotic tissues and that proinflammatory cytokines contribute to the development of endometriosis via up-regulation of CCL20 secretion from endometriotic stromal cells.
Hirata
Tetsuya
T
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Osuga
Yutaka
Y
Takamura
Masashi
M
Kodama
Ako
A
Hirota
Yasushi
Y
Koga
Kaori
K
Yoshino
Osamu
O
Harada
Miyuki
M
Takemura
Yuri
Y
Yano
Tetsu
T
Taketani
Yuji
Y
D000704:Analysis of Variance; D002465:Cell Movement / Q000502:physiology; D054418:Chemokine CCL20 / Q000378:metabolism*; D004715:Endometriosis / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D010049:Ovarian Diseases / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D054418:Chemokine CCL20; D020381:Interleukin-17; D053583:Interleukin-1beta; D054399:Receptors, CCR6; D014409:Tumor Necrosis Factor-alpha