S5a binds to death receptor-6 to induce THP-1 monocytes to differentiate through the activation of the NF-κB pathway.
Analyses of supernatants from apoptotic cells have helped in the identification of many signals that modulate the states of cell activation and differentiation. However, the current knowledge about the soluble factors that are released during apoptosis is rather limited. Previous studies have shown that S5a and angiocidin (both encoded by PSMD4) induce human acute monocytic leukemia cells (THP-1 cells) to differentiate into macrophages, but the cell-surface receptor of S5a has not been identified. In this study, we show that apoptotic THP-1 cells release endogenous S5a that binds to death receptor-6 (DR6, also known as TNFRSF1), which was identified as an orphan receptor, to induce THP-1 cells to differentiate. Furthermore, we found that the NF-κB pathway is activated, and that the transcription factors WT1 (Wilms' tumor 1) and c-myb mediate S5a-induced THP-1 differentiation. We also show that differentiation is blocked by anti-DR6 antibody, DR6 siRNA, DR6-Fc, NF-κB inhibitor or WT1 siRNA treatment. Our findings indicate that the interaction between cells can determine their differentiation, and we provide evidence for a functional interaction between S5a and DR6, which provides a novel potential mechanism to induce the differentiation of cancer cells, especially during biotherapy for leukemia.
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Zheng
Z
Wang
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Chen
C
Fan
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Hong-Fei
HF
Zhou
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Jian-Sheng
JS
Lu
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Ming-Juan
MJ
Sun
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Jing-Wen
JW
Song
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Yuan
Y
Le
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
Hong-Die
HD
Jiang
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China wsh928@hotmail.com jiaobh@live.cn.
Liang-Hua
LH
Wang
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China wsh928@hotmail.com jiaobh@live.cn.
Bing-Hua
BH
Jiao
D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D006801:Humans; D009000:Monocytes / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*
D019138:Antibodies, Blocking; D016328:NF-kappa B; C498506:PSMD4 protein, human; D020598:Proto-Oncogene Proteins c-myb; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; C114109:TNFRSF21 protein, human; D025721:WT1 Proteins; D046988:Proteasome Endopeptidase Complex
DR6; Differentiation; NF-κb; S5a; THP-1 cells