title: IL-35 over-expression increases apoptosis sensitivity and suppresses cell growth in human cancer cells.
abstract: Interleukin (IL)-35 is a novel heterodimeric cytokine in the IL-12 family and is composed of two subunits: Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35. IL-35 is expressed in T regulatory (Treg) cells and contributes to the immune suppression function of these cells. In contrast, we found that both IL-35 subunits were expressed concurrently in most human cancer cell lines compared to normal cell lines. In addition, we found that TNF-α and IFN-γ stimulation led to increased IL-35 expression in human cancer cells. Furthermore, over-expression of IL-35 in human cancer cells suppressed cell growth in vitro, induced cell cycle arrest at the G1 phase, and mediated robust apoptosis induced by serum starvation, TNF-α, and IFN-γ stimulation through the up-regulation of Fas and concurrent down-regulation of cyclinD1, survivin, and Bcl-2 expression. In conclusion, our results reveal a novel functional role for IL-35 in suppressing cancer activity, inhibiting cancer cell growth, and increasing the apoptosis sensitivity of human cancer cells through the regulation of genes related to the cell cycle and apoptosis. Thus, this research provides new insights into IL-35 function and presents a possible target for the development of novel cancer therapies.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Long
authors.forename: Xulong
authors.initials: X
authors.lastname: Zhang
authors.forename: Mingjie
authors.initials: M
authors.lastname: Wen
authors.forename: Qingli
authors.initials: Q
authors.lastname: Kong
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lv
authors.forename: Yunqing
authors.initials: Y
authors.lastname: An
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Wei
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis*; D007378:Interleukins / Q000096:biosynthesis*; D015778:Minor Histocompatibility Antigens; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: C107489:BIRC5 protein, human; C530104:CCND1 protein, human; C097732:EBI3 protein, human; C491901:FAS protein, human; D051034:Inhibitor of Apoptosis Proteins; D053765:Interleukin-12 Subunit p35; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; D019938:Cyclin D1; D007371:Interferon-gamma