Tuyt L M, Dokter W H, Birkenkamp K, Koopmans S B, Lummen C, Kruijer W, Vellenga E
Division of Hematology, Department of Medicine, University of Groningen, The Netherlands.
J Immunol. 1999 Apr 15;162(8):4893-902.
In the present study we investigated the possible involvement of the mitogen-activated protein kinase family members extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene expression in human monocytes, in particular their role in enhancing NF-kappa B activity. Freshly isolated monocytes treated with the protein phosphatase inhibitor okadaic acid secreted high levels of IL-6 protein, which coincided with enhanced binding activity of NF-kappa B as well as with phosphorylation and activation of the ERK1/2 and JNK proteins. The ERK pathway-specific inhibitor PD98059 inhibited IL-6 secretion from monocytes. Transient overexpression of inactive mutants of either Raf-1 or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity. By using PD98059, we demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DNA binding of NF-kappa B but, rather, acted at the level of transcriptional activity of NF-kappa B. Interestingly, it was shown that NF-kappa B-mediated gene transcription, both in the context of the IL-6 promoter as well as on its own, was dependent on both serine kinase activity and interaction with c-Jun protein. We conclude that okadaic acid-induced IL-6 gene expression is at least partly mediated through the ERK1/2 and JNK pathway-dependent activation of NF-kappa B transcriptional capacity. Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun.
在本研究中，我们调查了丝裂原活化蛋白激酶家族成员细胞外调节激酶1/2（ERK1/2）和c-Jun氨基末端激酶（JNK）在介导人单核细胞中白细胞介素-6（IL-6）基因表达中的可能作用，特别是它们在增强核因子-κB（NF-κB）活性方面的作用。用蛋白磷酸酶抑制剂冈田酸处理新鲜分离的单核细胞可分泌高水平的IL-6蛋白，这与NF-κB结合活性增强以及ERK1/2和JNK蛋白的磷酸化和激活同时发生。ERK途径特异性抑制剂PD98059抑制单核细胞分泌IL-6。Raf-1或JNK1无活性突变体的瞬时过表达表明，这两条途径均参与κB依赖性IL-6启动子活性。通过使用PD98059，我们证明Raf1/MEK1/ERK1/2途径不影响NF-κB的DNA结合，而是在NF-κB转录活性水平起作用。有趣的是，研究表明，无论是在IL-6启动子背景下还是单独情况下，NF-κB介导的基因转录均依赖于丝氨酸激酶活性以及与c-Jun蛋白的相互作用。我们得出结论，冈田酸诱导的IL-6基因表达至少部分是通过ERK1/2和JNK途径依赖性激活NF-κB转录能力介导的。我们的结果表明，JNK途径可能通过其对c-Jun的磷酸化和激活来调节NF-κB介导的基因转录。
