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

JOURNAL OF CLINICAL INVESTIGATION

Volume 123, Issue 3, Pages 1019-1031

AMER SOC CLINICAL INVESTIGATION INC

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.

Medicine, Research & Experimental

1. Ministry of Education, Culture, Sports, Science, and Technology of Japan
2. Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation
3. Deutsche Forschungsgemeinschaft [SFB841, TP C1, SFB576, TP A10, AL1174/3-1]
4. Cluster of Excellence - Inflammation at Interfaces
5. Else Kroner Fresenius Stiftung [2010-A144]
6. [Sonderforschungsbereich 576]
7. [A 10]