Results
| PMID | 21546388 |
| Gene Name | IL6 |
| Condition | Endometriosis |
| Association |
Associated |
| Sex | Female |
| Associated genes | IL-6 |
| Other associated phenotypes |
Endometriosis |
|
Hum Reprod. 2011 Jul;26(7):1892-8. doi: 10.1093/humrep/der125. Epub 2011 May 5. Saito, Ako| Osuga, Yutaka| Yoshino, Osamu| Takamura, Masashi| Hirata, Tetsuya| Hirota, Yasushi| Koga, Kaori| Harada, Miyuki| Takemura, Yuri| Yano, Tetsu| Taketani, Yuji Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan. BACKGROUND: Proteinase-activated receptor 2 (PAR2) is a G-protein-coupled receptor that is activated by several serine proteases. PAR2 activation in endometriotic stromal cells (ESCs) has been implicated in the development of endometriosis but the regulatory mechanism of PAR2 expression in ESC is unknown. Our objective was to study the mechanism by which PAR2 expression may be regulated in endometriotic lesions. METHODS: Primary cultures of ESCs were treated with transforming growth factor-beta (TGF-beta) 1, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and the expression of PAR2 was examined by real-time quantitative PCR. ESCs pretreated with or without TGF-beta1 were treated with PAR2 agonist peptide (PAR2AP) and the secretion of the pro-endometriotic cytokine, IL-6, was measured using a specific enzyme-linked immunosorbent assay. Effects of TGF-beta type 1 inhibitor, SB431542, and PAR2 small interfering RNA (siRNA) on the TGF-beta1 stimulation of PAR2 gene expression and PAR2AP-induced IL-6 secretion were also evaluated. To study intracellular signaling, effects of inhibitors of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) and of Smad4 siRNA on the TGF-beta1-induced PAR2 gene expression were studied. RESULTS: Only TGF-beta1, but neither TNF-alpha nor IL-1beta, increased gene expression of PAR2. Activation of PAR2 with PAR2AP increased the secretion of IL-6 from ESCs. As expected, TGF-beta1 pretreatment dose-dependently enhanced the PAR2AP-induced increase in IL-6 secretion from ESCs. Treatment of ESCs with the TGF-beta type 1 inhibitor, SB431542, inhibited both TGF-beta1-stimulation of PAR2 gene expression and PAR2AP-induced IL-6 secretion. Transfection of ESCs with PAR2 siRNA produced a similar inhibition of IL-6 secretion. The TGF-beta1-induced increase in PAR2 gene expression was repressed by inhibition of p38 MAPK, p42/44 MAPK or PI3K, but not by knockdown of Smad4 expression. CONCLUSIONS: In view of significant roles of PAR2 and IL-6 in endometriosis, the TGF-beta1-induced increase in PAR2 expression may be an elaborate mechanism that augments the progression of the disease. Mesh Terms: Endometriosis/*metabolism/pathology| Enzyme-Linked Immunosorbent Assay| Female| Gene Expression Regulation/drug effects| Humans| Interleukin-1beta/metabolism| Interleukin-6/*secretion| MAP Kinase Signaling System/drug effects| Phosphatidylinositol |
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