Z Gastroenterol 2015; 53 - A1_36
DOI: 10.1055/s-0034-1397077

MK2 mediates induction and sensing of Oncostatin M-induced intercellular signalling in the liver but is dispensable for negative feedback regulation via SOCS3

O Böhmer 1, C Ehlting 1, MJ Hahnel 1, M Thomas 2, UM Zanger 2, M Gaestel 3, WT Knoefel 4, J Schulte am Esch 4, D Häussinger 1, JG Bode 1
  • 1Heinrich-Heine University Hospital, Department of Gastroenterology, Hepatology and Infectious Diseases, Duesseldorf, Germany
  • 2Robert Bosch Hospital, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
  • 3Hannover Medical School, Institute of Physiological Chemistry, Hannover, Germany
  • 4Heinrich-Heine University Hospital, Department of Surgery, University Hospital, Duesseldorf, Germnay

Oncostatin M (OSM) is expressed in the context of several inflammatory diseases and plays a role in liver regeneration after liver injury. It is mainly secreted by activated T lymphocytes, monocytes and macrophages such as the Kupffer cells of the liver. As a member of the IL-6-type cytokine family it is also involved in the regulation of acute phase protein expression in hepatocytes. Binding of OSM to its cognate receptor complex, activates several signaling cascades. This includes signals mediated via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and those mediated via mitogen-activated protein kinase (MAPK) activating kinase (MEK)1 and subsequent activation of extracellular signal regulated kinase (ERK)1 and 2. Apart from this OSM also strongly induces activation of p38MAPK and its down-stream effector kinase MAPK activated protein kinase (MK)2.

Our data reveal that in macrophages MK2 is required to produce OSM in response to inflammatory stimuli such as lipopolysaccharides (LPS). Of note, although macrophages are able to produce OSM, they are not able to sense OSM since they lack the β subunit of the OSM receptor (OSMRβ). Contrariwise, in hepatocytes MK2 negatively controls the availability of the OSMRβ subunit, which is highly expressed in hepatocytes. Hence, during LPS-induced inflammation OSM represents a one-directional signal released from the macrophages and sensed by hepatocytes. Interestingly, the data suggest that MK2 controls both the intensity of the signal as well as the receptiveness of the recipient. Thereby MK2 controls the receptiveness of hepatocytes towards OSM at the receptor level, but not at the level of feed back regulators of intracellular signalling, such as suppressor of cytokine signalling (SOCS)3. Evidence is provided that the regulation of the OSM-induced expression of this major endogenous negative regulator of STAT3 signalling involves MEK-1- and Erk1/2-dependent stabilization of the SOCS transcript but does not require MK2.

Thus, in the context of liver injury MK2 is essential for the induction and sensing of OSM-mediated intercellular signaling between macrophages and hepatocytes, but it is dispensable for intracellular negative feedback regulation of the STAT3-dependent intra-cellular signal-transduction of OSM.

Corresponding author: Bode, Johannes G.

E-Mail: johannes.bode@med.uni-duesseldorf.de