Pawate Siddharama, Bhat Narayan R
Department of Neurosciences, Medical University of South Carolina, Charleston, 29425, USA.
Antioxid Redox Signal. 2006 May-Jun;8(5-6):903-9. doi: 10.1089/ars.2006.8.903.
The mitogen-activated protein kinases (MAPKs) play a central role in mediating the activation and transcriptional responses of diverse cells, including glia. c-Jun N-terminal kinase (JNK), a member of the MAPK family, is activated by a variety of stress and proinflammatory signals and in turn phosphorylates its downstream substrates including nuclear factors, leading to transcriptional activation of target genes. There are at least three subtypes of JNK (i.e., JNKs 1-3) that may play isoform-specific roles. This study examined the role of JNK isoforms in the induction of inducible nitric oxide synthase (iNOS) in astrocytes in response to lipopolysachharide (LPS) and interferon (IFN)-gamma. While an inhibitor of the JNK pathway (SP600125) inhibited iNOS expression, ectopic expression of a constitutively active form of MEKK1 (MAPK/ERK kinase kinase- 1), an upstream activator of JNK, led to an induction of co-transfected iNOS promoter activity and, in the presence of LPS, to an enhanced expression of iNOS. RNA knockdown studies with JNK subtype-specific short-interfering RNA (siRNA), indicated that JNK1- but not JNK2- nor JNK3-specific siRNA, interfered with LPS/IFNgamma induction of iNOS. It is concluded that, of the three JNK forms, JNK1 is the major mediator of iNOS induction and perhaps, inflammatory signaling in general, in glial cells.
丝裂原活化蛋白激酶（MAPK）在介导包括神经胶质细胞在内的多种细胞的激活和转录反应中发挥核心作用。c-Jun氨基末端激酶（JNK）是MAPK家族的成员之一，可被多种应激和促炎信号激活，进而使其下游底物（包括核因子）磷酸化，导致靶基因的转录激活。JNK至少有三种亚型（即JNK1-3），它们可能发挥亚型特异性作用。本研究检测了JNK亚型在星形胶质细胞中对脂多糖（LPS）和干扰素（IFN）-γ反应时诱导型一氧化氮合酶（iNOS）表达中的作用。虽然JNK途径的抑制剂（SP600125）抑制了iNOS的表达，但JNK的上游激活剂、持续激活形式的MEKK1（MAPK/ERK激酶激酶-1）的异位表达导致共转染的iNOS启动子活性增加，并且在存在LPS的情况下，导致iNOS表达增强。使用JNK亚型特异性小干扰RNA（siRNA）的RNA敲低研究表明，JNK1特异性siRNA而非JNK2或JNK3特异性siRNA干扰了LPS/IFNγ诱导的iNOS表达。得出的结论是，在三种JNK形式中，JNK1是神经胶质细胞中iNOS诱导以及可能一般炎症信号传导的主要介质。
