IL-17 and IL-6 Trans-Signaling Coordinate Mesothelial Vascular Endothelial Growth Factor Production and Angiogenesis...

Peritoneal angiogenesis is a key determinant of long-term peritoneal dialysis outcomes, yet the contribution of IL-17 remains unclear. This study examined the association between IL-17 and peritoneal vascularity in patients undergoing peritoneal dialysis and defined mechanisms linking IL-17 to vascular endothelial growth factor (VEGF) expression in human peritoneal mesothelial cells. Peritoneal biopsies showed sparse IL-17 expression, but IL-17 positivity correlated with increased IL-6 and VEGF expression and higher CD31⁺ microvessel density, indicating a coordinated pro-angiogenic network. In vitro, IL-17 induced IL-6 mRNA and protein in human peritoneal mesothelial cells in a time- and dose-dependent manner but did not directly stimulate VEGF. However, combined IL-17 and soluble IL-6 receptor markedly increased VEGF mRNA, promoter activity, and protein secretion, consistent with IL-6 trans-signaling. Genetic or antibody-mediated inhibition of IL-6 abolished VEGF induction, confirming IL-6 dependency. Mechanistically, VEGF induction by IL-17 + soluble IL-6 receptor was mediated by STAT3 and was independent of specificity protein 4 (SP4), despite IL-6-dependent SP4 up-regulation. Promoter analysis identified a VEGF region (-1290/-791) required for responsiveness, containing activator protein 1 (AP-1) and NF-κB binding sites. STAT3 acted upstream of AP-1 activation through induction of cellular Fos proto-oncogene protein (c-FOS), whereas NF-κB contributed directly to promoter activation and indirectly by enhancing IL-6 expression. These findings identify IL-17 as an indirect driver of peritoneal angiogenesis via IL-6 trans-signaling and coordinated STAT3, AP-1, and NF-κB activation.