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IL-6 trans-signaling links inflammation with angiogenesis in the peritoneal membrane

Catar, Rusan, Witowski, Janusz, Zhu, Nan, Lücht, Christian, Derrac Soria, Alicia, Uceda Fernandez, Javier, Chen, Lei, Jones, Simon, Fielding, Ceri A., Rudolf, Andras, Topley, Nicholas, Dragun, Duska and Jörres, Achim 2017. IL-6 trans-signaling links inflammation with angiogenesis in the peritoneal membrane. Journal of the American Society of Nephrology 28 (4) , pp. 1188-1199. 10.1681/ASN.2015101169

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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 of Sp4 and Vegf 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Lippincott, Williams & Wilkins
ISSN: 1046-6673
Funders: Arthritis Research UK, British Council
Date of First Compliant Deposit: 5 May 2017
Date of Acceptance: 19 September 2016
Last Modified: 19 Oct 2019 07:25

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