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 signal-transducing 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-1β 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 down-regulation 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.

• Authors: Nora Honke, Kim Ohl, Anastasia Wiener, Jeff Bierwagen, Joachim Peitz, Stefano Di Fiore, Rainer Fischer, Norbert Wagner, Stefan Wüller, Klaus Tenbrock
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 66 Issue 2 Pg. 470-8 (Feb 2014) ISSN: 2326-5205 [Electronic] United States
• PMID: 24504821 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 by the American College of Rheumatology.

Chemical References

• Interleukin-1beta
• Interleukin-6
• SOCS3 protein, human
• STAT3 Transcription Factor
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Cytokine Receptor gp130
• Serine
• p38 Mitogen-Activated Protein Kinases

Topics

• Adolescent
• Arthritis, Juvenile (pathology, physiopathology)
• Cells, Cultured
• Child
• Cytokine Receptor gp130 (physiology)
• Down-Regulation (physiology)
• Flow Cytometry
• Humans
• In Vitro Techniques
• Interleukin-1beta (physiology)
• Interleukin-6 (physiology)
• Monocytes (pathology, physiology)
• Phosphorylation (physiology)
• STAT3 Transcription Factor (physiology)
• Serine (metabolism)
• Signal Transduction (physiology)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (physiology)
• Synovial Fluid (cytology, physiology)
• p38 Mitogen-Activated Protein Kinases (physiology)