IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality
(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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https://lup.lub.lu.se/record/3657317
- author
- organization
- publishing date
- 2013
- 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}}, }