The p38‐Mediated Rapid Down‐Regulation of Cell Surface gp130 Expression Impairs Interleukin‐6 Signaling in the Synovial Fluid of Juvenile Idiopathic Arthritis Patients

Abstract

Objective. Interleukin-6 (IL-6) signaling plays an important proinflammatory role, but this role is restricted by regulatory mechanisms that, for example, reduce the cell surface availability of the signaltransducing chain of the IL-6 receptor, gp130. The aim of this study was to determine whether the inflammatory environment in arthritic joints has an impact on monocytic gp130 surface expression and the extent to which regulatory processes in the synovial fluid (SF) can be reproduced in an in vitro model.Methods. Flow cytometry and live cell imaging were used to measure the cell surface expression and internalization of gp130. STAT-3 phosphorylation was monitored by flow cytometry and Western blotting.Results. In patients with juvenile idiopathic arthritis (JIA), levels of cell surface gp130 expression in SF monocytes were reduced compared to those in peripheral blood (PB) monocytes. These reduced levels were reproduced when PB monocytes from healthy donors were stimulated with SF, and this reduction was dependent on p38 MAPK. The induction of p38 by IL-1␤ in PB monocytes interfered with IL-6 signaling due to the reduced cell surface expression of gp130.Conclusion. These results suggest that p38-mediated proinflammatory stimuli induce the downregulation of gp130 on monocytes and thus restrict gp130-mediated signal transduction. This regulatory mechanism could be of relevance to processes in the inflamed joints of patients with JIA.

Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation

“…In juvenile idiopathic arthritis, gp130 expression was reduced in monocytes and dependent on p38 MAPK activation ( 28 ) while it was increased in CD4 + T cells in synovial tissue (but not in synovial fluid). This increase in T cells was dependent on IL-10 secretion ( 29 ).…”

Interleukin-6 in juvenile idiopathic arthritis

“…The involvement of IL-6 is supported by the clinical finding that treatment with IL-6 inhibitor restored NK cytotoxic activity in JIA patients [29]. In monocytes, IL-6 signaling is inhibited with reduced expression of membranous IL-6R and gp130, mainly due to suppression of p38 MAPK signaling by IL-1b stimuli [30]. Besides, IL-6 modifies cytokine profile in JIA synoviocytes with pro-inflammatory and anti-inflammatory manners [31].…”

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

“…For example, gp130 expression is downregulated during granulocyte differentiation 42 and upon activation of T cells. 43 Moreover, pre-stimulation with IL-1b reduces gp130 availability at the surface of human hepatocytes 44 or monocytes 45 in a p38-dependent manner. Therefore, Molecular Therapy: Nucleic Acids we investigated if the effects of miR-16-1-3p, miR-4473, and miR-520f-3p on gp130 were sufficient to modulate the activation of STAT3 upon hy-IL-6 stimulation.…”