The Affect Of P38MAPK Inhibitor In The Progress Of SLE

Systemic lupus erythematosus(SLE) is a kind of autoimmune disease with inflammatory cytokines playing an important role in its pathogenesis.Mitogen-activated protein kinases(MAPK) are key protein kinases that mediate cellular responses to stress and injury signals.One major group of MAPK cascades is p38MAPK which can regulate inflammatory cytokines production.Objective:To investigate the role of p38MAPK in the pathogenesis of SLE and to determine the efficacy and safety of p38MAPK inhibitor in SLE animal model.Method:The expression of the phosphorylated p38MAPK in peripheral blood T lymphocytes of active SLE patients and volenteers was analysed by flow cytometry (FCM).ELISA was carried out to evaluate the levels of TNF-αproduction in ConA-stimulated peripheral blood T lymphocytes of SLE patients and volenteers under various doses of p38MAPK inhibitor.In animal model,urinary protein content,liver and kidney function,kidney/body weight and spleen/body weight ratio,glomerular immunocomplex deposition and pathological changes of kidney,liver and spleen were evaluated in MRL/lpr mice with or without oral p38MAPK inhibitor.Results:The expression of phosphorylated p38MAPK in peripheral blood T lymphocytes of active SLE patients was significantly higher than that of volenteers,the levels of TNF-αexpression in T lymphocytes from peripheral blood of SLE patients and volenteers coluld be selectively inhibited by p38MAPK inhibitor SB203580.The urinary protein content,kidney/body weight ratio,BUN values and glomerular IgA,IgG and IgM immunocomplex deposition were decreased significantly in MRL/lpr mice with treatment of SB203580.Mild pathological changes of kidney and liver in treated mice were also found.Conclutions:Excessive p38MAPK activation in peripheral blood T lymphocytes of active SLE patients indicates an aberrant T lymphocyte activation.TNF-αexpression of lymphocytes is regulateded by p38MAPK.p38MAPK inhibitor can reduce TNF-αproduction and may lead to the control of the inflammation and tissue injury in the MRL/lpr mice model.No significant liver or kidney side effects were observed in p38MAPK inhibitor SB203580 treated MRL/lpr mice.Our data may favour the further clinical study of p38MAPK inhibitor SB203580 in treatment of SLE,especially lupus nephritis.