title: Tyr³²³-dependent p38 activation is associated with rheumatoid arthritis and correlates with disease activity.
abstract: OBJECTIVE
  The p38 MAPK is important in the pathogenic immune response in rheumatoid arthritis (RA). The p38 molecule can be activated through phosphorylation on Thr¹⁸⁰-Tyr¹⁸² by upstream MAPK kinases and via an alternative pathway through phosphorylation on Tyr³²³. We undertook this study to quantify the phosphorylation of Tyr³²³ p38 and of Thr¹⁸⁰-Tyr¹⁸² p38 on T cells from healthy controls and patients with RA or ankylosing spondylitis (AS) to identify variables associated with p38 phosphorylation and disease activity.
  
  
  METHODS
  We measured p38 phosphorylation on Tyr³²³ and Thr¹⁸⁰-Tyr¹⁸² by flow cytometry and Western blotting on T cells from 30 control subjects, 33 AS patients, 30 patients with RA in remission, and 79 patients with active RA. We collected the clinical characteristics and analyzed correlations between clinical variables, the Disease Activity Score in 28 joints (DAS28), and p38 phosphorylation levels. Multivariate regression analysis was performed to identify variables associated with p38 phosphorylation on Tyr³²³ and Thr¹⁸⁰-Tyr¹⁸².
  
  
  RESULTS
  Phosphorylation of p38 on Tyr³²³ was higher in T cells from patients with active RA (P = 0.008 versus healthy controls) than in patients with RA in remission or in patients with AS. Tyr³²³ p38 phosphorylation was associated with disease activity determined by the DAS28 (P = 0.017). Enhanced p38 phosphorylation was linked to Lck-mediated activation of the Tyr³²³-dependent pathway in the absence of upstream MAPKK activation.
  
  
  CONCLUSIONS
  Our results indicate that phosphorylation status on Tyr³²³ p38 correlates with RA disease activity and suggest that the Tyr³²³-dependent pathway is an attractive target for down-regulation of p38 activity in RA patients.
authors: Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
authors: Mercedes
authors: M
authors: López-Santalla
authors: María
authors: M
authors: Salvador-Bernáldez
authors: Isidoro
authors: I
authors: González-Alvaro
authors: Santos
authors: S
authors: Castañeda
authors: Ana M
authors: AM
authors: Ortiz
authors: María Isabel
authors: MI
authors: García-García
authors: Leonor
authors: L
authors: Kremer
authors: Fernando
authors: F
authors: Roncal
authors: Juan
authors: J
authors: Mulero
authors: Carlos
authors: C
authors: Martínez-A
authors: Jesús M
authors: JM
authors: Salvador
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D010766:Phosphorylation; D012044:Regression Analysis; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D014443:Tyrosine / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases