Modulation of the IL-6-Signaling Pathway in Liver Cells by miRNAs Targeting gp130, JAK1, and/or STAT3

Abstract

Interleukin-6 (IL-6)-type cytokines share the common receptor glycoprotein 130 (gp130), which activates a signaling cascade involving Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) transcription factors. IL-6 and/or its signaling pathway is often deregulated in diseases, such as chronic liver diseases and cancer. Thus, the identification of compounds inhibiting this pathway is of interest for future targeted therapies. We established novel cellular screening systems based on a STAT-responsive reporter gene ( Cypridina luciferase ). Of a library containing 538 microRNA (miRNA) mimics, several miRNAs affected hyper-IL-6-induced luciferase activities. When focusing on candidate miRNAs specifically targeting 3′ UTRs of signaling molecules of this pathway, we identified, e.g., miR-3677-5p as a novel miRNA affecting protein expression of both STAT3 and JAK1, whereas miR-16-1-3p, miR-4473, and miR-520f-3p reduced gp130 surface expression. Interestingly, combination treatment with 2 or 3 miRNAs targeting gp130 or different signaling molecules of the pathway did not increase the inhibitory effects on phospho-STAT3 levels and STAT3 target gene expression compared to treatment with single mimics. Taken together, we identified a set of miRNAs of potential therapeutic value for cancer and inflammatory diseases, which directly target the expression of molecules within the IL-6-signaling pathway and can dampen inflammatory signal transduction.

IL-6 signalling protects zebrafish larvae duringStaphylococcus epidermidisinfection in a novel bath immersion model

“…Given the importance of IL-6 signalling in the host immune response to S.epidermidis infection, we investigated the mechanism(s) of IL-6 regulation. The IL-6 signalling pathway is regulated by multiple miRNAs (Servais et al, 2019). miR-142 is one of the major miRNAs that has been shown to have important functions in infections and inflammation (Shrestha et al, 2017).…”

“…miRNA-mediated modulation is one of the important mechanisms of regulation of different genes of this pathway (Tanaka et al, 2016). miR-142 is one of the several miRNAs that has been shown to be involved in the IL-6 signalling pathway (Servais et al, 2019). miR-142-3p has been reported to target il-6 in models of endotoxin-challenge and age-related studies (Liu et al, 2016; Sun et al, 2011).…”

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

“…29,30 Our findings indicated that the biological behaviour of osteoclasts is modulated by WKYMVm. [36][37][38] Moreover, CD9 stabilizes gp130 to activate STAT3 in glioma stem cells by preventing its ubiquitin-dependent lysosomal degradation. The NF-κB signalling pathway is considered essential for osteoclast differentiation and maturation.…”

Anti-Gastric Cancer Effect of Purified Omphalia Lapidescens Protein via Regulating the JAK/STAT3 Signaling Pathway

“…The JAK/STAT3 pathway transmits extracellular information to the nucleus to modulate cell proliferation, apoptosis, differentiation and angiogenesis [19][20].…”