Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Los Angeles, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
Mutagenesis. 2012 Jan;27(1):77-86. doi: 10.1093/mutage/ger063. Epub 2011 Oct 6.
Chronic inflammatory diseases are characterised by systemically elevated levels of tumour necrosis factor (TNF)-α, a proinflammatory cytokine with pleiotropic downstream effects. We have previously demonstrated increased genotoxicity in peripheral leukocytes and various tissues in models of intestinal inflammation. In the present study, we asked whether TNF-α is sufficient to induce DNA damage systemically, as observed in intestinal inflammation, and whether tumour necrosis factor receptor (TNFR) signalling would be necessary for the resultant genotoxicity. In the wild-type mice, 500 ng per mouse of TNF-α was sufficient to induce DNA damage to multiple cell types and organs 1-h post-administration. Primary splenic T cells manifested TNF-α-induced DNA damage in the absence of other cell types. Furthermore, TNFR1(-/-)TNFR2(-/-) mice demonstrated decreased systemic DNA damage in a model of intestinal inflammation and after TNF-α injection versus wild-type mice, indicating the necessity of TNFR signalling. Nuclear factor (NF)-κB inhibitors were also able to decrease damage induced by TNF-α injection in wild-type mice. When TNF-α administration was combined with interleukin (IL)-1β, another proinflammatory cytokine, DNA damage persisted for up to 24 h. When combined with IL-10, an anti-inflammatory cytokine, decreased genotoxicity was observed in vivo and in vitro. TNF-α/TNFR-mediated signalling is therefore sufficient and plays a large role in mediating DNA damage to various cell types, subject to modulation by other cytokines and their mediators.
慢性炎症性疾病的特征是肿瘤坏死因子 (TNF)-α 的全身水平升高，TNF-α 是一种具有多种下游效应的促炎细胞因子。我们之前已经证明，在肠道炎症模型中，外周白细胞和各种组织中的遗传毒性增加。在本研究中，我们想知道 TNF-α 是否足以全身性地诱导 DNA 损伤，就像在肠道炎症中观察到的那样，以及肿瘤坏死因子受体 (TNFR) 信号是否是导致遗传毒性所必需的。在野生型小鼠中，每只小鼠 500ng TNF-α足以在给药后 1 小时诱导多种细胞类型和器官的 DNA 损伤。原发性脾 T 细胞在没有其他细胞类型的情况下表现出 TNF-α 诱导的 DNA 损伤。此外，与野生型小鼠相比，TNFR1(-/-)TNFR2(-/-) 小鼠在肠道炎症模型中和 TNF-α 注射后表现出全身 DNA 损伤减少，表明 TNFR 信号的必要性。核因子 (NF)-κB 抑制剂也能够减少野生型小鼠中 TNF-α 注射诱导的损伤。当 TNF-α 给药与另一种促炎细胞因子白细胞介素 (IL)-1β 联合使用时，DNA 损伤可持续长达 24 小时。当与抗炎细胞因子 IL-10 联合使用时，体内和体外观察到遗传毒性降低。因此，TNF-α/TNFR 介导的信号足以介导各种细胞类型的 DNA 损伤，并受其他细胞因子及其介质的调节。
