Research into the effects of steroidal anti-inflammatory drugs on MAP kinase activation and cytokine production

我们研究了类固醇抗炎药是否通过抑制MAP激酶的激活来抑制细胞因子的产生。类固醇抗炎药地塞米松对MAP激酶活性的影响。地塞米松(10和100 nM)处理大鼠肥大细胞系RBL-2H3细胞18h，可抑制抗原诱导的c-Jun氨基末端激酶(JNK)活性的升高。地塞米松可降低抗原刺激引起的c-jun的磷酸化。这些结果表明，地塞米松抑制了抗原诱导的JNK激活，从而抑制了转录因子AP-1.2的激活。MA-P激酶激活抑制剂对抗原诱导的IL-4产生的影响。P13-激酶抑制剂Wortmannin和LY294002抑制抗原诱导的p38MAP和JNK。Wortmannin和p38MAP激酶抑制剂抑制抗原诱导的IL-4mRNA水平和IL-4的产生。此外，可以抑制AP-1活性的维甲酸也会抑制IL-4的产生。这说明MAP激活的抑制或AP-1活性的抑制导致IL-4的产生受到抑制。地塞米松抑制抗原诱导的MAPK活化的机制。地塞米松抑制MAPKKK Raf-1的磷酸化，但不影响Raf-1的膜转位。结论类固醇抗炎药抑制IL-4产生的机制之一是抑制MAP激酶的激活。因此，抑制MAP激活的药物可能是一种新型的抗炎药物。

We examined whether steroidal anti-inflammatory drugs inhibit cytokine production through inhibition of MAP kinase activation.1. Effects of the steroidal anti-inflammatory drug dexamethasone on MAP kinase activation. Pretreatment of rat mast cell line RBL-2H3 cells with dexamethasone (10 and 100 nM) for 18 hinhibited the antigen-induced increase in c-Jun N-terminal kinase (JNK) activity. The phosphory-lation of c-Jun induced by the antigen stimulation was also reduced by pretreatment with dexamethasone. These findings indicate that dexamethasone inhibits the antigen-induced activation of JNK resulting in the inhibition of the activation of the transcription factor AP-1.2. Effects of the inhibitors of MA P kinase activation on the antigen-induced IL-4production.Wortmannin and LY294002, the P13-kinase inhibitors, inhibited the antigen-induced p38 MAP kinase and JNK.Wortmannin and p38 MAP kinase inhibitors inhibited both the antigen-induced increase in the IL-4 mRNA level and IL-4 production. In addition, retinoids, which can inhibit AP-1activity, also inhibit IL-4 production. Thus it is demonstrated that the inhibition of MAP kinase activation or the inhibition of AP-1 activity resulted in the inhibition of IL-4 production.3. The mechanisms by which dexamethasone inhibits the antigen-induced MAPkinase activation. Dexamethasone inhibited the phosphorylation of MAPKKK Raf-1 without affecting Raf-1translocation to membrane fraction.ConclusionThese results suggested that one of the mechanisms by which steroidal anti-inflammatory drugs inhibits IL-4 production is the inhibition of MAP kinase activation. Thus, the drugs which inhibit MAP kinase activation might be a novel anti-inflammatory drugs.