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

Zhang, Hong ; Neuhoefer, Patrick ; Song, Liang ; Rabe, Bjoern ; Lesina, Marina ; Kurkowski, Magdalena U. ; Treiber, Matthias ; Wartmann, Thomas ; Regnér, Sara LU orcid and Thorlacius, Henrik LU , et al. (2013) In Journal of Clinical Investigation 123(3). p.1019-1031
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
123
issue
3
pages
1019 - 1031
publisher
The American Society for Clinical Investigation
external identifiers
  • wos:000315749400018
  • scopus:84874606609
  • pmid:23426178
ISSN
0021-9738
DOI
10.1172/JCI64931
language
English
LU publication?
yes
id
94346bd8-6b52-40d3-8b37-2b12352a7c51 (old id 3657317)
date added to LUP
2016-04-01 13:07:52
date last changed
2022-04-06 02:44:58
@article{94346bd8-6b52-40d3-8b37-2b12352a7c51,
  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.}},
  author       = {{Zhang, Hong and Neuhoefer, Patrick and Song, Liang and Rabe, Bjoern and Lesina, Marina and Kurkowski, Magdalena U. and Treiber, Matthias and Wartmann, Thomas and Regnér, Sara and Thorlacius, Henrik and Saur, Dieter and Weirich, Gregor and Yoshimura, Akihiko and Halangk, Walter and Mizgerd, Joseph P. and Schmid, Roland M. and Rose-John, Stefan and Alguel, Hana}},
  issn         = {{0021-9738}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{1019--1031}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality}},
  url          = {{https://lup.lub.lu.se/search/files/3176660/4025498.pdf}},
  doi          = {{10.1172/JCI64931}},
  volume       = {{123}},
  year         = {{2013}},
}