期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 3, 页码 1019-1031出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64931
关键词
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-kappa B 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.
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation
- Deutsche Forschungsgemeinschaft [SFB841, TP C1, SFB576, TP A10, AL1174/3-1]
- Cluster of Excellence - Inflammation at Interfaces
- Else Kroner Fresenius Stiftung [2010-A144]
- [Sonderforschungsbereich 576]
- [A 10]