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

Xiaoxiao Yang, Aiwu Lin, Na Jiang, Hao Yan, Zhaohui Ni, Jiaqi Qian, Wei Fang
Nephrology 2017, 22 (2): 150-158

AIMS: Interleukin-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.

METHODS: Human 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.

RESULTS: 1. 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.

CONCLUSION: The 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.

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