title: 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.
  
  
  CONCLUSIONS
  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: RWTH Aachen University, Aachen, Germany.
authors: Nora
authors: N
authors: Honke
authors: Kim
authors: K
authors: Ohl
authors: Anastasia
authors: A
authors: Wiener
authors: Jeff
authors: J
authors: Bierwagen
authors: Joachim
authors: J
authors: Peitz
authors: Stefano
authors: S
authors: Di Fiore
authors: Rainer
authors: R
authors: Fischer
authors: Norbert
authors: N
authors: Wagner
authors: Stefan
authors: S
authors: Wüller
authors: Klaus
authors: K
authors: Tenbrock
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D002648:Child; D050822:Cytokine Receptor gp130 / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology*; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology; D013582:Synovial Fluid / Q000166:cytology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases