Tyr323‐dependent p38 activation is associated with rheumatoid arthritis and correlates with disease activity

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2011-07, Vol.63 (7), p.1833-1842
• Main Authors: López‐Santalla, Mercedes, Salvador‐Bernáldez, María, González‐Alvaro, Isidoro, Castañeda, Santos, Ortiz, Ana M., García‐García, María Isabel, Kremer, Leonor, Roncal, Fernando, Mulero, Juan, Martínez‐A, Carlos, Salvador, Jesús M.
• Format: Article
• Language: English
• Subjects: Adult; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Biological and medical sciences; Blotting, Western; Diseases of the osteoarticular system; Female; Flow Cytometry; Humans; Inflammatory joint diseases; Kinases; Lymphocytes; Male; Medical sciences; Multivariate Analysis; p38 Mitogen-Activated Protein Kinases - immunology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Regression Analysis; Rheumatoid arthritis; Severity of Illness Index; Statistics, Nonparametric; Tyrosine - metabolism
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.30375

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. Conclusion 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.