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. , induction of peritoneal inflammation in wild-type and IL-6-deficient mice showed IL-6 involvement in the control of and expression 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.

Biocompatible Solutions and Long-Term Changes in Peritoneal Solute Transport

“…In keeping with previous research showing a robust association between intraperitoneal IL-6 production and faster PSTR (12,21,22), baseline dialysate IL-6 levels were associated with faster PSTR for the duration of follow-up, whereas plasma IL-6 had no effect. Although IL-6 has many immunomodulatory effects (23,24), recent observations linking IL-6 signaling to peritoneal VEGF production provide a mechanism by which IL-6, not itself vasoactive, might alter angiogenesis and vascular permeability in the peritoneal membrane (25).…”

Biomarker research to improve clinical outcomes of peritoneal dialysis: consensus of the European Training and Research in Peritoneal Dialysis (EuTRiPD) network

“…9 Importantly, experimental evidence in animal models links persistent peritoneal IL-6 generation to membrane change/fibrosis 10 and angiogenesis. 11 These processes may well bear clinical relevance as is suggested by the results of the Global Fluid Study, a multinational, multicenter, prospective, cohort study in 959 PD patients with up to 8 years of follow-up. Here it was found that local peritoneal and systemic inflammation are uncoupled, and that local, not systemic, inflammation is a main determinant of changes in peritoneal small solute transport rate that is observed over time.…”

Regulation of Hepatic MicroRNAs in Response to Early Stage Echinococcus multilocularis Egg Infection in C57BL/6 mice

“…In pathological situations, angiogenesis is driven by an immune reaction that includes the secretion of proinflammatory cytokines particularly IL-1β, TNF-α [104] and IL-6 [105]. Secretion of IL-1β, TNF-α and IL-6 is hallmark of the early inflammatory phase of AE observed in mice [84].…”