IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis–associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI.

Detaljer

Författare
  • Hong Zhang
  • Patrick Neuhoefer
  • Liang Song
  • Bjoern Rabe
  • Marina Lesina
  • Magdalena U. Kurkowski
  • Matthias Treiber
  • Thomas Wartmann
  • Sara Regnér
  • Henrik Thorlacius
  • Dieter Saur
  • Gregor Weirich
  • Akihiko Yoshimura
  • Walter Halangk
  • Joseph P. Mizgerd
  • Roland M. Schmid
  • Stefan Rose-John
  • Hana Alguel
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Kirurgi
Originalspråkengelska
Sidor (från-till)1019-1031
TidskriftJournal of Clinical Investigation
Volym123
Utgivningsnummer3
StatusPublished - 2013
PublikationskategoriForskning
Peer review utfördJa

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