Newton Robert, Shah Suharsh, Altonsy Mohammed O, Gerber Antony N
From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Alberta T2N 4Z6, Canada,
the Arnie Charbonneau Cancer Institute, Department of Oncology, University of Calgary, Alberta T2N 4Z6, Canada.
J Biol Chem. 2017 Apr 28;292(17):7163-7172. doi: 10.1074/jbc.R117.777318. Epub 2017 Mar 10.
Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid.
炎症信号诱导提供时间控制的反馈和前馈系统。虽然糖皮质激素可抑制炎症基因表达，但糖皮质激素受体的募集会增加负反馈和前馈调节因子的表达，包括磷酸酶DUSP1、泛素修饰酶TNFAIP3或mRNA不稳定蛋白ZFP36。此外，糖皮质激素受体与包括核因子-κB（NF-κB）在内的因子的协同作用可能会增强调节因子的表达以促进抑制作用。相反，被糖皮质激素抑制的丝裂原活化蛋白激酶（MAPKs）提供前馈控制以限制转录因子IRF1和趋化因子CXCL10的表达。我们提出，反馈和前馈控制的调节可决定炎症基因表达对糖皮质激素的抑制或抵抗。
