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

Authors

Rusan Catar, Edyta Kawka, Michael Adu-Gyamfi, Nada Al-Arawe, Pinchao Wang, Zexian Gong, Maria Bartosova Medvid, Joanna Żuraszek-Szymańska, Muhammad Imtiaz Ashraf, Bruno Ranchin, Julian Kamhieh-Milz, Honorata Stadnik, Marek Karczewski, Guido Moll, Claus Peter Schmitt, Achim Jörres, Janusz Witowski

Published in

The American journal of pathology. Sep 19, 2026. Epub Sep 19, 2026.

Abstract

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.

PMID:
42762971
Bibliographic data and abstract were imported from PubMed on 20 Sep 2026.

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