Liszewski Walter, Naym David Gram, Biskup Edyta, Gniadecki Robert
Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.
Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Photodermatol Photoimmunol Photomed. 2017 May;33(3):164-171. doi: 10.1111/phpp.12302. Epub 2017 Apr 17.
Photochemotherapy with psoralen and ultraviolet A (PUVA), with or without adjuvant interferon-α (IFN-α), is a first-line therapy for early-stage mycosis fungoides and other forms of cutaneous T-cell lymphoma (CTCL). However, the mechanism by which PUVA with IFN-α work in CTCL is poorly understood.
To develop a model to investigate the mechanisms of PUVA and PUVA with IFN-α in CTCL cells.
An in vitro model to study the molecular mechanisms of PUVA was created using two different CTCL cell lines, MyLa, which has functional p53, and HuT-78, in which p53 is inactivated due to a homozygous nonsense mutation.
PUVA caused G2/M cell cycle block and apoptosis of MyLa and HuT-78 accompanied by increase in the expression of the mitochondrial pro-apoptotic genes Bax, BAK, and PUMA and a downregulation in anti-apoptotic Bcl-2. p53 was induced and c-Myc was repressed by PUVA, but neither were essential for PUVA-induced apoptosis. IFN-α augmented PUVA-induced apoptosis via the JAK1 pathway, and this activity could be inhibited by ruxolitinib.
PUVA induces p53-independent apoptosis in CTCL cell lines, and this process is augmented by type I interferons via the JAK1 pathway.
补骨脂素与紫外线A（PUVA）光化学疗法，无论有无辅助性α干扰素（IFN-α），都是早期蕈样肉芽肿及其他形式皮肤T细胞淋巴瘤（CTCL）的一线治疗方法。然而，PUVA联合IFN-α在CTCL中的作用机制尚不清楚。
建立一个模型来研究PUVA及PUVA联合IFN-α在CTCL细胞中的作用机制。
利用两种不同的CTCL细胞系建立了一个体外模型，以研究PUVA的分子机制。一种是具有功能性p53的MyLa细胞系，另一种是HuT-78细胞系，其p53因纯合无义突变而失活。
PUVA导致MyLa和HuT-78细胞出现G2/M期细胞周期阻滞和凋亡，同时线粒体促凋亡基因Bax、BAK和PUMA的表达增加，抗凋亡基因Bcl-2的表达下调。PUVA可诱导p53表达并抑制c-Myc表达，但二者对PUVA诱导的凋亡均非必需。IFN-α通过JAK1途径增强PUVA诱导的凋亡，而鲁索替尼可抑制该活性。
PUVA在CTCL细胞系中诱导不依赖p53的凋亡，且这一过程可被I型干扰素通过JAK1途径增强。
