Oncostatin M induces RIG‐I and MDA5 expression and enhances the double‐stranded RNA response in fibroblasts

Abstract

Interleukin (IL)‐6‐type cytokines have no direct antiviral activity; nevertheless, they display immune‐modulatory functions. Oncostatin M (OSM), a member of the IL‐6 family, has recently been shown to induce a distinct number of classical interferon stimulated genes (ISG). Most of them are involved in antigen processing and presentation. However, induction of retinoic acid‐inducible gene (RIG)‐I‐like receptors (RLR) has not been investigated. Here we report that OSM has the capability to induce the expression of the DExD/H‐Box RNA helicases RIG‐I and melanoma differentiation antigen 5 (MDA5) as well as of the transcription factors interferon regulatory factor (IRF)1, IRF7 and IRF9 in primary fibroblasts. Induction of the helicases depends on tyrosine as well as serine phosphorylation of STAT1. Moreover, we could show that the OSM‐induced STAT1 phosphorylation is predominantly counter‐regulated by a strong STAT3‐dependent SOCS3 induction, as Stat3 as well as Socs3 knock‐down results in an enhanced and prolonged helicase and IRF expression. Other factors involved in regulation of STAT1 or IRF1 activity, like protein tyrosine phosphatase, non‐receptor type 2 (PTPN2), promyelocytic leukaemia protein (PML) or small ubiquitin‐related modifier 1 (SUMO1), play a minor role in OSM‐mediated induction of RLR. Remarkably, OSM and interferon‐γ (IFN‐γ) synergize to mediate transcription of RLR and pre‐treatment of fibroblasts with OSM fosters the type I interferon production in response to a subsequent encounter with double‐stranded RNA. Together, these findings suggest that the OSM‐induced JAK/STAT1 signalling is implicated in virus protection of non‐professional immune cells and may cooperate with interferons to enhance RLR expression in these cells.

OSMR gene effect on the pathogenesis of chronic autoimmune Urticaria via the JAK/STAT3 pathway

“…A previous study found that both type I and type II OSMR activated JAK1, JAK2, and TYK2 receptor-associated tyrosine kinases (Auguste et al, 1997 ). Recently, OSM has been reported to stimulate ISG genes participating in antigen processing as well as presentation (Hergovits et al, 2017 ). The OSMR protein has been reported to be capable of heterodimerizing with IL-6 signal transducer (gp130) in order to produce type II OSMR, and when the receptor complexes were taken in, JAK could be activated, followed by further activation of STAT3 (Hong et al, 2011 ).…”

The oncostatin M‐stromal cell axis in health and disease

“…However, dermal fibroblasts also respond to OSM by proliferating and increasing their production of extracellular matrix components, including collagen I, collagen III and various glycosaminoglycans . Furthermore, OSM induces expression of several classical interferon‐stimulated genes in dermal fibroblasts in a STAT1‐dependent manner, including the viral double‐stranded RNA sensors RIG‐I and MDA5, suggesting that it may be involved in antiviral immunity . Although OSM stimulation is sufficient to induce skin inflammation in vivo, it is dispensable in the imiquimod model of psoriasis‐like inflammation …”

“…[144][145][146] Furthermore, OSM induces expression of several classical interferon-stimulated genes in dermal fibroblasts in a STAT1-dependent manner, including the viral double-stranded RNA sensors RIG-I and MDA5, suggesting that it may be involved in antiviral immunity. 40 Although OSM stimulation is sufficient to induce skin inflammation in vivo, it is dispensable in the imiquimod model of psoriasis-like inflammation. 11,147 Like the joint, administration of exogenous OSM to the lower respiratory tract, either in the form of recombinant protein or OSM-encoding adenovirus, is sufficient to induce lung inflammation and tissue remodelling.…”

“…Because of their shared use of gp130, OSM unsurprisingly activates these same pathways. However, its distinct receptor architecture allows OSMR to robustly activate STAT1, STAT5 and possibly STAT6 . Furthermore, while gp130 activates ERK1/2 MAPK signalling via the adapter SHP‐2, OSMR recruits Shc, resulting in enhanced ERK1/2 activation and activation of p38 and JNK .…”

Single molecule poly(A) tail-seq shows LARP4 opposes deadenylation throughout mRNA lifespan with most impact on short tails

“…An ARE in LARP4 mRNA mediates decreased LARP4 levels in response to the cytokine tumor necrosis factor-α (TNFα) ( Mattijssen and Maraia, 2016 ). The type I interferon (IFN)-stimulated genes (ISGs) are induced by a variety of molecules including some interleukins, TNFα, and cytokines that activate various extracellular receptors ( Hergovits et al, 2017 ; Wang et al, 2016 ). ISGs are also induced by activation of intra cellular receptors in response to viral infection and other pathogens; different types of nucleic acids activate distinct pathways to ISG induction ( Atianand and Fitzgerald, 2013 ; Schneider et al, 2014 ).…”