ステロイド性抗炎症薬のｃ‐Ｊｕｎ Ｎ‐ｔｅｒｍｉｎａｌ ｋｉｎａｓｅ活性化抑制作用

Abstract

Effects of the steroidal anti-inflammatory drug dexamethasone on the antigeninduced activation of c-Jun N-terminal kinase (JNK) was examined. Antigen stimulation of IgE-sensitized rat basophilic leukemia RBL-2 H3 cells induced activation of JNK within a few minutes with maximum activity attained 40 min later. The increase in JNK activity was accompanied with an increase in phosphorylation of c-Jun in the cells. The antigen-induced JNK activation was inhibited by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY 294002 but not by the protein kinase C inhibitors calphostin C and Ro 31-8425. Pretreatment with dexamethasone (10 and 100 nM) for 18 h prominently inhibited the antigen-induced increase in JNK activity in a concentration-dependent manner, while protein levels of JNK were slightly decreased. At least 6-h preincubation with dexamethasone was necessary to inhibit the antigen-induced JNK activation. The phosphorylation of c-Jun induced by the antigen stimulation was reduced by pretreatment with dexamethasone without reduction of the content of c-Jun protein. The antigen-induced activation of the JNK kinase kinase MEKK-1 was also inhibited by pretreatment with dexamethasone. These findings indicate that dexamethasone inhibits the antigen-induced activation of JNK. In conclusion, the inhibition by dexamethasone of JNK activation resulting in the inhibition of c-Jun phosphorylation might be a new mechanism by which dexamethasone down-regulates AP-1 activity and inhibits cytokine production.