Kim Hun-Taek, Qiang Wenan, Liu Na, Scofield Virginia L, Wong Paul K Y, Stoica George
Department of Pathobiology, Texas A&M University, College Station, Texas 78957, USA.
J Neurovirol. 2005 Apr;11(2):166-79. doi: 10.1080/13550280590922810.
In susceptible strains of mice, infection with the mutant retrovirus MoMuLV-ts1 causes a neurodegeneration and immunodeficiency syndrome that resembles human human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS). In this study the authors show increased expression of cyclooxygenase-2 (COX-2) in the brainstem tissues of ts1-infected mice. Up-regulated central nervous system (CNS) levels of this enzyme are associated with HIV-associated dementia and other inflammatory and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In brainstem sections, the authors find that astrocytes surrounding spongiform lesions contain increased amounts of immunoreactive COX-2. COX-2 is also up-regulated in cultured ts1-infected cells from the C1 astrocytic cell line, and activation of c-Jun N-terminal kinase, or JNK, pathway. Markers of endoplasmic reticulum (ER) stress, specifically the CCAAT/enhancer-binding protein (CHOP), the glucose-related protein 78 (GRP78), and phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha), were also up-regulated in ts1-infected C1 astrocytes. Up-regulation of COX-2 and the above ER signaling factors was reversed by treatment of the infected cells with curcumin which specifically inhibits the JNK/c-Jun pathway. These findings indicate that the JNK/c-Jun pathway is most likely responsible for COX-2 expression induced by ts1 in astrocytes, and that ts1 infection in astrocytes may lead to up-regulation of both inflammatory and ER stress pathways in the central nervous system. Because COX-2 inhibitors are now widely used to treat inflammatory conditions in animals and humans, this finding suggests that these drugs may be useful for therapeutic intervention in neurodegenerative syndromes as well.
在易感染的小鼠品系中，感染突变逆转录病毒MoMuLV-ts1会引发一种神经退行性变和免疫缺陷综合征，类似于人类免疫缺陷病毒所致获得性免疫缺陷综合征（HIV-AIDS）。在本研究中，作者发现ts1感染小鼠的脑干组织中环氧合酶-2（COX-2）表达增加。该酶在中枢神经系统（CNS）中的上调水平与HIV相关痴呆以及其他炎症和神经退行性疾病如肌萎缩侧索硬化症、阿尔茨海默病和帕金森病有关。在脑干切片中，作者发现海绵状病变周围的星形胶质细胞含有增加量的免疫反应性COX-2。COX-2在来自C1星形胶质细胞系的培养ts1感染细胞中也上调，并且c-Jun氨基末端激酶（JNK）途径被激活。内质网（ER）应激标志物，特别是CCAAT/增强子结合蛋白（CHOP）、葡萄糖相关蛋白78（GRP78）和磷酸化真核起始因子2α（eIF2α）在ts1感染的C1星形胶质细胞中也上调。用姜黄素处理感染细胞可逆转COX-2和上述ER信号因子的上调，姜黄素可特异性抑制JNK/c-Jun途径。这些发现表明JNK/c-Jun途径很可能是ts1诱导星形胶质细胞中COX-2表达的原因，并且星形胶质细胞中的ts1感染可能导致中枢神经系统中炎症和ER应激途径的上调。由于COX-2抑制剂目前广泛用于治疗动物和人类的炎症性疾病，这一发现表明这些药物可能也有助于对神经退行性综合征进行治疗干预。
