Abstract
Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology.
Highlights
The interleukin-6-type cytokine oncostatin M (OSM) was initially described as a cytokine with strong growth inhibitory effects on melanoma cells [1]
Studies carried out by a number of research groups in the last decade have clearly shown that human and murine OSM signal in a species-specific manner: Human OSM (hOSM) can signal in human cells via two receptor complexes, the type I gp130/LIFR or the type II gp130/OSM receptor (OSMR) [32,33] complex, while mOSM only signals via the type II receptor complex [34]
It was shown that hOSM activates only the type I receptor complex on mouse cells and mOSM fails to activate signaling in human cells [34]
Summary
The interleukin-6-type cytokine oncostatin M (OSM) was initially described as a cytokine with strong growth inhibitory effects on melanoma cells [1]. Studies over the last decade have, suggested that it has pleiotropic activities. Contributions of this cytokine have been identified for hematopoietic progenitor cell homeostasis [2,3], extrathymic T cell development [4,5], suppression of fetal liver hematopoiesis [6,7], liver development [8,9] and regeneration [10], angiogenesis [11], cardiac remodeling [12] and for inflammatory processes. Human OSM (hOSM) is mainly expressed by neutrophils, activated macrophages, dendritic cells and T-cells [1,17,24,25] as a 252 amino acid precursor polypeptide [26]. A high homology exists to LIF [31]
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