Zhong Julia Li, Raval Chintan M, Nisar Muhammad Farrukh, Bian ChunXiang, Zhang Jin, Yang Li, Tyrrell Rex M
The Base of "111 Project" for Biomechanics and Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, 400044, China; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK; Dermatology Institute, Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Photochem Photobiol. 2014 Nov-Dec;90(6):1340-8. doi: 10.1111/php.12343. Epub 2014 Oct 27.
UVA treatment of cultured human skin fibroblasts (FEK4) has been shown previously to reduce transcriptional activation of heme oxygenase 1 (HO-1) following a second dose of UVA radiation, a phenomenon known as refractoriness. This study demonstrates that the levels of HO-1 protein are also reduced after a second dose of UVA radiation as are Nrf2 levels, and there is less accumulation of Nrf2 in the nucleus where as Bach1 does accumulate in the nucleus. Cell viability is further reduced and cell membrane damage increased as compared with a single UVA treatment when an initial UVA treatment was followed by a second dose. Knockdown of Nrf2 by siRNA (siNrf2) targeting caused additional refractoriness of HO-1 protein induction to a second UVA or heme treatment and this treatment also further enhanced cell damage by a second dose of UVA radiation. However, transfection with Nrf2 caused less refractoriness of HO-1 to a second dose of UVA and reduced cell damage by a second dose of UVA radiation. These findings are consistent with the proposal that Nrf2 is involved in HO-1 refractoriness and could serve as a cytoprotective factor against cell damage caused by repeated exposure to moderate doses of UVA radiation. We propose that protection by the Nrf2-HO-1 pathway protection may have clinical relevance since human skin is exposed repeatedly to UVA radiation.
先前的研究表明，用紫外线A（UVA）处理培养的人皮肤成纤维细胞（FEK4）后，再给予第二剂UVA辐射，会降低血红素加氧酶1（HO-1）的转录激活，这一现象称为不应性。本研究表明，第二剂UVA辐射后，HO-1蛋白水平以及核因子E2相关因子2（Nrf2）水平也会降低，且Nrf2在细胞核中的积累减少，而Bach1确实会在细胞核中积累。与单次UVA处理相比，当初始UVA处理后再给予第二剂时，细胞活力进一步降低，细胞膜损伤增加。通过靶向小干扰RNA（siRNA）敲低Nrf2会导致HO-1蛋白诱导对第二剂UVA或血红素处理产生额外的不应性，并且这种处理还会因第二剂UVA辐射而进一步增强细胞损伤。然而，转染Nrf2会使HO-1对第二剂UVA的不应性降低，并减少第二剂UVA辐射造成的细胞损伤。这些发现与Nrf2参与HO-1不应性的观点一致，并且可以作为一种细胞保护因子，抵御因反复暴露于中等剂量UVA辐射而导致的细胞损伤。我们认为，由于人类皮肤会反复暴露于UVA辐射，Nrf2-HO-1途径的保护作用可能具有临床意义。
