title: IL-6 Trans-Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane.
abstract: Vascular endothelial growth factor (VEGF) is implicated in the peritoneal membrane remodeling that limits ultrafiltration in patients on peritoneal dialysis (PD). Although the exact mechanism of VEGF induction in PD is unclear, VEGF concentrations in drained dialysate correlate with IL-6 levels, suggesting a link between these cytokines. Human peritoneal mesothelial cells (HPMCs), the main source of IL-6 and VEGF in the peritoneum, do not bear the cognate IL-6 receptor and are thus unable to respond to classic IL-6 receptor signaling. Here, we investigated whether VEGF release by HPMCs is controlled by IL-6 in combination with its soluble receptor (IL-6 trans-signaling). Although treatment with either IL-6 or soluble IL-6 receptor (sIL-6R) alone had no effect on VEGF production, stimulation of HPMCs with IL-6 in combination with sIL-6R promoted VEGF expression and secretion through a transcriptional mechanism involving STAT3 and SP4. Conditioned medium from HPMCs cultured with IL-6 and sIL-6R promoted angiogenic endothelial tube formation, which could be blocked by silencing SP4.In vivo, induction of peritoneal inflammation in wild-type and IL-6-deficient mice showed IL-6 involvement in the control ofSp4andVegfexpression and new vessel formation, confirming the role of IL-6 trans-signaling in these processes. Taken together, these findings identify a novel mechanism linking IL-6 trans-signaling and angiogenesis in the peritoneal membrane.
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
authors.forename: Rusan
authors.initials: R
authors.lastname: Catar
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Witowski
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lücht
authors.affiliation: Division of Infection and Immunity and.
authors.forename: Alicia
authors.initials: A
authors.lastname: Derrac Soria
authors.affiliation: Division of Infection and Immunity and.
authors.forename: Javier
authors.initials: J
authors.lastname: Uceda Fernandez
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Infection and Immunity and.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Division of Infection and Immunity and.
authors.forename: Ceri A
authors.initials: CA
authors.lastname: Fielding
authors.affiliation: Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Andras
authors.initials: A
authors.lastname: Rudolf
authors.affiliation: Division of Infection and Immunity and.|Wales Kidney Research Unit, Cardiff University School of Medicine, Cardiff, United Kingdom; and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany; JoerresA@kliniken-koeln.de.|Department of Medicine I, Nephrology, Transplantation and Medical Intensive Care, University Witten/Herdecke, Medical Center Cologne-Merheim, Cologne, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Jörres
mesh_terms: D000818:Animals; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic; D010537:Peritoneum / Q000098:blood supply*; D010538:Peritonitis / Q000209:etiology*; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D042461:Vascular Endothelial Growth Factor A; C577686:interleukin-6, mouse
keywords: Cell Signaling; peritoneal dialysis; peritoneal membrane; vascular endothelial growth factor