title: Development of refractoriness of HO-1 induction to a second treatment with UVA radiation and the involvement of Nrf2 in human skin fibroblasts.
abstract: 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.
authors.affiliation: 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.
authors.forename: Julia Li
authors.initials: JL
authors.lastname: Zhong
authors.forename: Chintan M
authors.initials: CM
authors.lastname: Raval
authors.forename: Muhammad Farrukh
authors.initials: MF
authors.lastname: Nisar
authors.forename: ChunXiang
authors.initials: C
authors.lastname: Bian
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Rex M
authors.initials: RM
authors.lastname: Tyrrell
mesh_terms: D002478:Cells, Cultured; D004790:Enzyme Induction; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects*; D014466:Ultraviolet Rays
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051547:Heme Oxygenase-1