Alterations in oncostatin M receptor expression is associated with the progression of non-alcoholic fatty liver disease

One of the cytokine families most prominently associated with liver inflammation, obesity and metabolic response, is the family of IL-6-type cytokines, in particular IL-6 itself, but also its less well-investigated relative oncostatin M (OSM). IL-6 and OSM have been shown to be intimately connected with our body”s reaction to physical, metabolic and pathogen-induced stress. Reports over the last two decades have clearly pointed out that these cytokines have anti-inflammatory as well as pro-inflammatory signaling activities which very much depend on the cellular and physiological context in which they are released or the receptors they utilize for signaling. Much attention has been given to IL-6 as well as its mode of action, however, recent studies implicate that OSM is much more strongly involved in disease pathogenesis than anticipated so far. Its physiology, however, is far less well understood.

Question OSM can signal via two receptor complexes which might have more pro- or anti-inflammatory activities, respectively. Here, we addressed the question whether alterations in receptor expression become evident in NAFLD progression.

Methods We characterized the expression profile of the type I and type II OSM receptor complex in liver samples from different rodent models of liver inflammation or in vitro in hepatoma cell lines stimulated with different inflammatory cytokines using quantitative real-time PCR, Western blot analysis and flow cytometry.

Results We found a distinct decrease of components of the type I OSM receptor complex in livers from mice fed a high-fat diet, after intraperitoneal injection of TNFα or IL-1β or upon cholestasis. At the same time the type II OSM receptor complex appeared to be strongly upregulated. Similar observations were made in HepG2 cells treated with IL-1β. Application of pharmacological inhibitors to prevent activation of distinct mitogen-activated protein kinase pathways (ERK1/2 or p38) demonstrated the necessity of ERK1/2 activity to modulate the expression of the type I OSM receptor complex.

Conclusions Dysregulation of the expression levels of the type I and type II OSM receptor complexes appears to be a conserved feature in the progression of inflammatory liver diseases. Consequently, alterations in OSM receptor levels might be a possible diagnostic marker for the assessment of progressive liver inflammation.

Publication History

Article published online:
04 January 2021