Involvement of NADPH oxidase and NF-κB activation in CXCL1 induction by vascular endothelial growth factor in human endometrial epithelial cells of patients with adenomyosis.
Chemokines were known to participate in inflammation and angiogenesis but have been recently recognized to be involved in embryonic implantation and endometrium-related pathologies. Among these chemokines, the CXC chemokines, such as CXCL1, have potential roles to work as biomarkers to identify patients with uterine adenomyosis. In this study, human endometrial epithelial cells (HEECs) were derived from patients' endometrium with adenomyosis. The inductive effects of CXCL1 production by various mediators/growth factors were investigated in the HEECs. Of the tested mediators, VEGF was found to be the most effective. The immunohistochemistry and RT-PCR analysis revealed a positive staining for VEGF and CXCL1 at the epithelium and the presence of CXCL1 in the human endometrium specimens, respectively. The CXCL1 induction by VEGF could be reduced by the antagonist for VEGF receptor (VEGFR), and by the inhibitors for NADPH oxidase and NF-κB signaling pathway. However, it was not affected by sex hormones and the inhibitors for MAPKs, PI-3K, protein kinase A and C. In parallel, VEGF induced p47 phox NADPH oxidase activation, IκBα phosphorylation, NF-κB translocation and NF-κB-DNA complex formation in the HEECs. Moreover, the CXCL1 released by the HEECs with VEGF stimulation attracted vascular endothelial cell migration. Taken together, we show that VEGF and CXCL1 are expressed in epithelium of the endometrium with adenomyosis and demonstrate here for the first time that VEGF is capable of inducing CXCL1 expression in HEECs through VEGFR, p47 phox NADPH oxidase and NF-κB signaling pathway, which is functionally required for attracting vascular endothelial cell migration.
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei City, Taiwan; Institute of Systems Biology and Bioinformatics, National Central University, Zhongli District, Taoyuan City, Taiwan.
Tsung-Hsuan
TH
Lai
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
Pi-Hui
PH
Wu
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan. Electronic address: wenbin@mail.fju.edu.tw.
Wen-Bin
WB
Wu
D062788:Adenomyosis / Q000276:immunology*; D002465:Cell Movement; D054360:Chemokine CXCL1 / Q000378:metabolism*; D004717:Endometrium / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D019255:NADPH Oxidases; D040262:Receptors, Vascular Endothelial Growth Factor
Cellular signaling; Chemokine; Endometrium; Epithelial cells; Gro-α; NF-κB; VEGF