IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality
Hong Zhang, … , Stefan Rose-John, Hana Algül
Hong Zhang, … , Stefan Rose-John, Hana Algül
Published February 15, 2013
Citation Information: J Clin Invest. 2013;123(3):1019-1031. https://doi.org/10.1172/JCI64931.
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Research Article Immunology

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

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.

Authors

Hong Zhang, Patrick Neuhöfer, Liang Song, Björn Rabe, Marina Lesina, Magdalena U. Kurkowski, Matthias Treiber, Thomas Wartmann, Sara Regnér, Henrik Thorlacius, Dieter Saur, Gregor Weirich, Akihiko Yoshimura, Walter Halangk, Joseph P. Mizgerd, Roland M. Schmid, Stefan Rose-John, Hana Algül

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Figure 1

IL-6 levels correlate with the extent of pulmonary damage and lethality during SAP.

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IL-6 levels correlate with the extent of pulmonary damage and lethality ...
(A) Schematic model for SAP. (B and C) Histological sections of H&E-stained pancreatic and lung tissue of C57BL/6 mice at the indicated time points. Note the increase of edema (asterisk) and necrosis (white arrowheads) in the pancreas after 8 hours and 3 days and the first signs of regeneration of damaged pancreatic tissue (black arrowheads) after 3 days. Lung damage continued to increase after 3 days, as demonstrated by alveolar wall thickening and collapse (see higher-magnification views of boxed regions at far right; enlarged ×3). (D) MPO activity in lung tissue of C57BL/6 mice (n = 5). (E) Flow cytometry analysis of CD11b+/Gr-1+ cells in total lung tissue (n = 6) and cytospin preparation of BALF in C57BL/6 mice. (F) Lung permeability, evaluated by FITC-dextran clearance. (G) Interstitial fluid accumulation, measured as capillary-alveolar membrane thickness (n = 10). (H–K) Total cell count (H), total protein concentration (I), BALF CXCL1 (J), and BALF IL-6 (K) (n = 1–3 per condition; 4 independent experiments). (L and M) Serum levels of IL-6 (L) and CXCL1 (M) in C57BL/6 mice (n > 5). (N) Kaplan-Meier curves of cerulein-treated Il6–/– mice (green; n = 5) and of C57BL/6 mice treated with cerulein (black; n = 6), cerulein plus 5 μg/d recombinant IL-6 (blue; n = 5), or NaCl sham plus 5 μg/d recombinant IL-6 (purple; n = 5). Results represent mean ± SD. *P < 0.05, **P < 0.005, ***P < 0.001. Scale bars: 50 μm.