Karin Michael
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
Proc Am Thorac Soc. 2005;2(4):386-90; discussion 394-5. doi: 10.1513/pats.200504-034SR.
Given the prevalence and debilitating nature of chronic inflammatory diseases, there is a never-ending quest to identify novel targets for the rational development of antiinflammatory drugs. The major signaling pathway that controls inflammation-associated gene expression is the one which leads to activation of transcription factor nuclear factor-kappaB. Therefore, inhibitors of the kinase responsible for nuclear factor-kappaB activation, IkappaB kinase, are expected to have potent antiinflammatory activity. Indeed, our results with cell type-specific inactivation of the beta-catalytic subunit of IkappaB kinase are by and large consistent with this assertion. In addition to IkappaB kinase and nuclear factor-kappaB, the expression of certain proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, is dependent on mitogen-activated protein kinases. Therefore, considerable attention has also been given to mitogen-activated protein kinases as likely targets for the development of novel antiinflammatory therapeutics. Preliminary preclinical data suggest that inhibitors that target all these pathways exhibit antiinflammatory activity. This review focuses on the possible mechanisms through which such inhibitors may interfere with inflammation and some of the complications that may be associated with their use.
鉴于慢性炎症性疾病的普遍性及其使人衰弱的特性，人们一直在不断探索确定新的靶点，以便合理开发抗炎药物。控制炎症相关基因表达的主要信号通路是导致转录因子核因子-κB激活的通路。因此，负责核因子-κB激活的激酶即IκB激酶的抑制剂有望具有强大的抗炎活性。事实上，我们对IκB激酶β催化亚基进行细胞类型特异性失活的研究结果大体上与这一论断相符。除了IκB激酶和核因子-κB外，某些促炎细胞因子如白细胞介素-1和肿瘤坏死因子-α的表达还依赖于丝裂原活化蛋白激酶。因此，丝裂原活化蛋白激酶作为新型抗炎治疗药物可能的靶点也受到了相当多的关注。临床前初步数据表明，针对所有这些通路的抑制剂均具有抗炎活性。本综述重点关注此类抑制剂可能干扰炎症的机制以及与其使用相关的一些并发症。
