Interleukin‐6 trans‐signalling induces vascular endothelial growth factor synthesis partly via Janus kinases‐STAT3 pathway in human mesothelial cells

• DOI: 10.1111/nep.12746
• Publication Date: 2016-02-12T08:12:24Z
• Authors: Xiaoxiao Yang; Aiwu Lin; Na Jiang; Hao Yan; Zhaohui Ni; Jiaqi Qian; Wei Fang
• Keywords: STAT3 Transcription Factor; Vascular Endothelial Growth Factor A; 0301 basic medicine; Time Factors; Dose-Response Relationship, Drug; Interleukin-6; Active Transport, Cell Nucleus; Epithelial Cells; Hep G2 Cells; Tyrphostins; Receptors, Interleukin-6; Up-Regulation; 03 medical and health sciences; Glucose; Cytokine Receptor gp130; Humans; Mannitol; Phosphorylation; Protein Kinase Inhibitors; Janus Kinases; Signal Transduction

AbstractAimsInterleukin‐6 (IL‐6) is a vital inflammatory factor in the peritoneal cavity of peritoneal dialysis (PD) patients. Because intraperitoneal inflammation is closely associated with angiogenesis, we sought to explore the effect of IL‐6 on vascular endothelial growth factor (VEGF) synthesis and its transduction pathway in mesothelial cells.MethodsHuman mesothelial cells (Met‐5A) were incubated with different concentrations of glucose and mannitol, and the effect of glucose and mannitol on the expression of IL‐6 was determined. Then, the cells were stimulated by IL‐6 with or without two soluble receptors of IL‐6 (sIL‐6R or sgp130), and VEGF synthesis was detected. Finally, the cells were incubated with IL‐6/sIL‐6R combined with or without the inhibitor of Janus kinases (JAK) AG490. The phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and its intracellular translocation were examined.Results1. High glucose and mannitol could upregulate IL‐6 mRNA expression and IL‐6 secretion in mesothelial cells significantly, and there was no difference of its effect between high glucose and mannitol. 2. Met‐5A was a cell line with a single IL‐6 receptor. The IL‐6/sIL‐6R complex induced VEGF synthesis of mesothelial cells, which was alleviated by sgp130 or AG490. IL‐6 trans‐signalling could induce the phosphorylation of STAT3, which is recruited to the cellular nucleus of Met‐5A cells.ConclusionThe present study might provide evidence that high glucose upregulates IL‐6 synthesis in Met‐5A cells, to some extent, depending on its osmolality and that IL‐6 trans‐signalling could induce VEGF synthesis partly dependent on the JAK/STAT3 pathway.