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.
Highlights
Activation of pattern recognition receptors (PRR) is the first line of defence against infection by pathogens
A preliminary microarray-based screening experiment performed with Oncostatin M (OSM)-treated human dermal fibroblasts (HDF, not shown) indicated that OSM might induce the expression of a panel of interferon stimulated genes (ISG), including the RIG-I-like receptors (RLR) retinoic acid-inducible gene (RIG)-I and melanoma differentiation antigen 5 (MDA5), as well as the transcription factor IRF1
RIG-I-like receptors (RLR) are cytoplasmic RNA helicases, which are expressed at low levels in resting cells, but their expression is strongly induced during viral infection by secretion of type I interferons [6, 54] as well as proinflammatory cytokines including IFN-c, IL-1b and TNF [4, 9, 11,12,13,38,39,55,56]
Summary
Activation of pattern recognition receptors (PRR) is the first line of defence against infection by pathogens. While resting cells show relatively low levels of RLR, their expression is strongly induced after viral infection and exposure to type I. OSM, another member of the IL-6-type cytokine family, was shown to induce a distinct number of classical interferon target genes (ISG) [18]. In combination with type I IFNs, OSM synergized in the inhibition of HCV and HAV infection in hepatoma cells by an enhanced expression of a subset of ISG as well as induction of immune stimulatory molecules like IL-7 and IL-15R, which are implicated in T-cell effector functions [19,20,21]. OSM is produced by activated monocytes and macrophages [22, 23], but can be released by neutrophils and dendritic cells upon stimulation with LPS or granulocyte/macrophage-colony stimulating factor (GM-CSF)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
