Matkovic Urska, Pacenti Monia, Trevisan Marta, Palù Giorgio, Barzon Luisa
Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Padova, Italy.
J Cell Physiol. 2009 Jul;220(1):45-57. doi: 10.1002/jcp.21727.
After systemic administration, adenoviral vectors (AdVs) are sequestered in the liver and adrenal glands. Adenoviral vector transduction has been shown to cause cytopathic effects on human hepatocytes and to induce an inflammatory response, whereas the effect of AdVs on human adrenocortical cells has never been investigated. In this study, human adrenocortical carcinoma cell lines and primary cell cultures were used to assess the effects of wild-type adenovirus (Ad5WT) and E1/E3-deleted AdVs on cell proliferation and steroidogenesis. Ad5WT could efficiently replicate in adrenocortical cells, leading to S phase induction, followed by cell death, whereas high titer AdVs transduction had only mild effects on adrenocortical cell proliferation, with accumulation of cells in G2/M. Both AdVs and Ad5WT induced expression of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, but, most importantly, they led to a marked and dose-dependent increase of cortisol and other steroid hormone production and consistently modulated expression of key steroidogenic enzymes and regulators of steroidogenesis. This effect, which was already apparent at 6 h post-infection, probably represented a response to adenoviral entry and/or early phases of infection. The result of this study contribute to the understanding of host response to adenoviral vector administration.
全身给药后，腺病毒载体（AdV）会在肝脏和肾上腺中蓄积。腺病毒载体转导已被证明会对人肝细胞产生细胞病变效应并引发炎症反应，而AdV对人肾上腺皮质细胞的影响尚未得到研究。在本研究中，使用人肾上腺皮质癌细胞系和原代细胞培养物来评估野生型腺病毒（Ad5WT）和E1/E3缺失的AdV对细胞增殖和类固醇生成的影响。Ad5WT能够在肾上腺皮质细胞中有效复制，导致S期诱导，随后细胞死亡，而高滴度AdV转导对肾上腺皮质细胞增殖只有轻微影响，细胞在G2/M期积累。AdV和Ad5WT均诱导炎性细胞因子如白细胞介素-6和肿瘤坏死因子-α的表达，但最重要的是，它们导致皮质醇和其他类固醇激素产生显著且呈剂量依赖性增加，并持续调节关键类固醇生成酶和类固醇生成调节因子的表达。这种效应在感染后6小时就已明显，可能代表了对腺病毒进入和/或感染早期阶段的反应。本研究结果有助于理解宿主对腺病毒载体给药的反应。
