Increased ERK and JNK activation and decreased ERK/JNK ratio are associated with long-term organ damage in patients with systemic lupus erythematosus

Objective: The activities of two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), correlate with disease severity in SLE patients. Whether they are also associated with long-term organ damage is unknown. The aim of the present work was to determine whether impaired expression and activity of ERK and JNK correlate with long-term damage in SLE. Methods: The expression of ERK and JNK and their phosphorylated active forms was determined by western blot analysis four times during the first year of follow-up in peripheral blood mononuclear cells from 36 SLE patients. A correlation analysis was performed between ERK and JNK expression and long-term organ damage estimated by the SLICC/ARC Damage Index (SDI) 4 years later. Results: Mean levels of ERK and JNK activities during the first year correlated with long-term organ damage severity (r = 0.38 and r = 0.35, respectively; P = 0.05). Overall JNK expression increased with the severity of chronic damage (P = 0.01; P = 0.05 for SDI score 2 and 3, respectively). In contrast, overall ERK expression significantly decreased in patients with maximal organ damage (SDI score 3) compared with patients with an SDI score of 2 (P = 0.03). The ERK/JNK ratio decreased by approximately 40% and 30% in patients with an SDI score of 3 as compared with patients without organ damage and healthy controls, respectively. Conclusion: These results demonstrate that early activation of ERK and JNK along with decreased overall ERK expression and reduced ERK/JNK ratio may predict the severity of long-term organ damage in SLE patients.