National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St., London SW3 6LY, UK.
Proc Am Thorac Soc. 2009 Dec;6(8):693-6. doi: 10.1513/pats.200907-071DP.
Epigenetic modification of gene expression by methylation of DNA and various post-translational modifications of histones may affect the expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases activates inflammatory genes, whereas histone deacetylation results in inflammatory gene repression. Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes, but mainly by recruiting histone deacetylase-2 (HDAC2) to activated inflammatory genes. HDAC2 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma. In chronic obstructive pulmonary disease (COPD), there is resistance to the antiinflammatory actions of corticosteroids, which is explained by reduced activity and expression of HDAC2. This can be reversed by a plasmid vector, which restores HDAC2 levels, but may also be achieved by low concentrations of theophylline. Oxidative stress causes corticosteroid resistance by reducing HDAC2 activity and expression by activation of phosphoinositide-3-kinase-delta, resulting in HDAC2 phosphorylation via a cascade of kinases. Theophylline reverses corticosteroid resistance by directly inhibiting oxidant-activated PI3Kdelta and is mimicked by PI3Kdelta knockout or by selective inhibitors. Other treatments may also interact in this pathway, making it possible to reverse corticosteroid resistance in patients with COPD, as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate. Other histone modifications, including methylation, tyrosine nitration, and ubiquitination may also affect histone function and inflammatory gene expression, and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies, particularly in corticosteroid-resistant inflammation.
DNA 甲基化和组蛋白各种翻译后修饰对基因表达的表观遗传修饰可能会影响多个炎症基因的表达。组蛋白乙酰转移酶使组蛋白乙酰化会激活炎症基因，而组蛋白去乙酰化则会导致炎症基因的抑制。皮质类固醇通过诱导抗炎基因的乙酰化发挥其抗炎作用，但主要是通过招募组蛋白去乙酰化酶 2（HDAC2）到激活的炎症基因。HDAC2 去乙酰化乙酰化的糖皮质激素受体，使它们能够抑制哮喘中的激活炎症基因。在慢性阻塞性肺疾病（COPD）中，皮质类固醇的抗炎作用存在抵抗，这可以通过 HDAC2 活性和表达的降低来解释。这可以通过质粒载体来逆转，该载体可以恢复 HDAC2 水平，但也可以通过低浓度茶碱来实现。氧化应激通过激活磷酸肌醇-3-激酶-δ（PI3Kδ）来降低 HDAC2 活性和表达，从而导致 HDAC2 通过激酶级联反应磷酸化，从而导致皮质类固醇抵抗。茶碱通过直接抑制氧化应激激活的 PI3Kδ 来逆转皮质类固醇抵抗，并通过 PI3Kδ 敲除或选择性抑制剂来模拟。其他治疗方法也可能在该途径中相互作用，从而有可能逆转 COPD 患者、哮喘吸烟者和某些患有严重哮喘的患者中的皮质类固醇抵抗，这些患者中存在类似的机制。其他组蛋白修饰，包括甲基化、酪氨酸硝化和泛素化，也可能影响组蛋白功能和炎症基因表达，更好地了解这些表观遗传途径可能会导致新的抗炎治疗方法，特别是在皮质类固醇抵抗性炎症中。
