title: Interferon-γ produced by tumor-infiltrating NK cells and CD4+ T cells downregulates TNFSF15 expression in vascular endothelial cells.
abstract: Endothelial cells in an established vasculature secrete tumor necrosis factor superfamily-15 (TNFSF15; VEGI; TL1A) that functions as a negative modulator of neovascularization to maintain blood vessel stability. TNFSF15 gene expression diminishes at angiogenesis and inflammation sites such as in cancers and wounds. We reported previously that vascular endothelial growth factor and monocyte chemotactic protein-1 contribute to TNFSF15 downmodulation in ovarian cancer. Here we show that interferon-γ (IFNγ) suppresses TNFSF15 expression in human umbilical vein endothelial cells. This activity is mediated by IFNγ receptor and the transcription factor STAT1. Immunohistochemical analysis of ovarian cancer clinical specimens indicates that TNFSF15 expression diminishes while tumor vascularity increases in specimens with high-grades of IFNγ expression. Since tumor-infiltrating NK and CD4(+) T cells are the main sources of IFNγ in tumor lesions, we isolated these cells from peripheral blood of healthy individuals, treated the cells with ovarian cancer OVCAR3 cell-conditioned media, and found a onefold and tenfold increase of IFNγ production in NK and CD4(+) T cells, respectively, compared with that in vehicle-treated cells. These findings support the view that tumor-infiltrating NK and CD4(+) T cells under the influence of cancer cells significantly increase the production of IFNγ, which in turn inhibits TNFSF15 expression in vascular endothelial cells, shifting the balance of pro- and anti-angiogenic factors toward escalated angiogenesis potential in the tumor.
authors.affiliation: College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Juan
authors.initials: J
authors.lastname: Song
authors.forename: Xiulong
authors.initials: X
authors.lastname: Niu
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Qin
authors.forename: Weimin
authors.initials: W
authors.lastname: Deng
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000378:metabolism*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human; C117026:TNFSF15 protein, human