IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality
| Autor: | Björn Rabe, Magdalena U. Kurkowski, Patrick Neuhöfer, Walter Halangk, Stefan Rose-John, Akihiko Yoshimura, Roland M. Schmid, Marina Lesina, Liang Song, Thomas Wartmann, Hong Zhang, Matthias Treiber, Gregor Weirich, Hana Algül, Henrik Thorlacius, Dieter Saur, Sara Regnér, Joseph P. Mizgerd |
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| Rok vydání: | 2013 |
| Předmět: |
STAT3 Transcription Factor
Chemokine CXCL1 animal diseases Acute Lung Injury Mice Transgenic Acinar Cells Lung injury Receptors Interleukin-8B Sepsis Mice medicine Animals Humans Myeloid Cells Phosphorylation Receptor Interleukin 6 Pancreas biology Interleukin-6 business.industry Phenylurea Compounds Benzenesulfonates NF-kappa B General Medicine respiratory system medicine.disease Receptors Interleukin-6 Pathophysiology respiratory tract diseases Mice Inbred C57BL CXCL1 Aminosalicylic Acids Pancreatitis Immunology biology.protein Acute pancreatitis Surgery business Protein Processing Post-Translational Signal Transduction Research Article |
| Zdroj: | Journal of Clinical Investigation; 123(3), pp 1019-1031 (2013) |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci64931 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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