IL-17 and IL-6 trans-signaling coordinate mesothelial VEGF production and angiogenesis in the peritoneum

Peritoneal angiogenesis is a key determinant of long-term peritoneal dialysis (PD) outcomes, yet the contribution of interleukin-17 (IL-17) remains unclear. This study examined the association between IL-17 and peritoneal vascularity in PD patients and defined mechanisms linking IL-17 to vascular endothelial growth factor (VEGF) expression in human peritoneal mesothelial cells (HPMCs). 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 HPMCs in a time- and dose-dependent manner but did not directly stimulate VEGF. However, combined IL-17 and soluble IL-6 receptor (sIL-6R) 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+sIL-6R was mediated by STAT3 and was independent of SP4, despite IL-6-dependent SP4 upregulation. Promoter analysis identified a VEGF region (-1290/-791) required for responsiveness, containing AP-1 and NF-κB binding sites. STAT3 acted upstream of AP-1 activation through induction of c-FOS, while 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.