lterations in type I and type II oncostatin M receptor expression in the pathogenesis of non-alcoholic fatty liver disease

Background:

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.

Methods:

Since OSM can signal via two receptor complexes which might have more pro- or anti-inflammatory activities, respectively, we characterized their expression profile in vivo 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 or after intraperitoneal injection of TNFα or IL-1β. 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.