title: 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: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors: Hong
authors: H
authors: Zhang
authors: Patrick
authors: P
authors: Neuhöfer
authors: Liang
authors: L
authors: Song
authors: Björn
authors: B
authors: Rabe
authors: Marina
authors: M
authors: Lesina
authors: Magdalena U
authors: MU
authors: Kurkowski
authors: Matthias
authors: M
authors: Treiber
authors: Thomas
authors: T
authors: Wartmann
authors: Sara
authors: S
authors: Regnér
authors: Henrik
authors: H
authors: Thorlacius
authors: Dieter
authors: D
authors: Saur
authors: Gregor
authors: G
authors: Weirich
authors: Akihiko
authors: A
authors: Yoshimura
authors: Walter
authors: W
authors: Halangk
authors: Joseph P
authors: JP
authors: Mizgerd
authors: Roland M
authors: RM
authors: Schmid
authors: Stefan
authors: S
authors: Rose-John
authors: Hana
authors: H
authors: Algül
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D055371:Acute Lung Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D054360:Chemokine CXCL1 / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; D016328:NF-kappa B; C520337:NSC 74859; D010671:Phenylurea Compounds; D019947:Receptors, Interleukin-6; D023063:Receptors, Interleukin-8B; C112019:SB 225002; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C577686:interleukin-6, mouse