Carcinogenesis Advance Access originally published online on April 17, 2009
Carcinogenesis 2009 30(6):1064-1072; doi:10.1093/carcin/bgp095
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Differential effects of arsenic on cutaneous and systemic immunity: focusing on CD4+ cell apoptosis in patients with arsenic-induced Bowen's disease
1 Graduate Institute of Medicine, Kaohsiung Medical University
2 Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China
3 Department of Internal Medicine and Institute of Molecular Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan, Republic of China
4 Department of Dermatology, Kaohsiung Medical University, No. 100 Shih Chuan 1st Road, Kaohsiung 807, Taiwan, Republic of China
5 Department of Dermatology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung 814, Taiwan, Republic of China
6 Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan, Republic of China
7 Department of Clinical Pathology, Chang Gung Memorial Hospital--Kaohsiung Medical Center, Niaosong Township, Kaohsiung County 833, Taiwan, Republic of China
* To whom correspondence should be addressed. Tel: +886 7 3117820; Fax: +886 7 3212062; Email: dermyu{at}kmu.edu.tw
Bowen's disease (BD), a carcinoma in situ of the skin, has been identified as an early lesion in arsenic carcinogenesis. Patients with arsenic-induced Bowen's disease (As-BD) showed both cutaneous and systemic immune dysfunctions. We set out to evaluate the interactions between keratinocytes and lymphocytes in the context of As-BD carcinogenesis. Our results showed that As-BD lesions demonstrated a significant dermal CD4+ cell, an essential regulator of proper tumor immunity, undergoing apoptosis. In addition, it was found that the As-BD patients have lower percentage of peripheral CD4+ cells as compared with control subjects. However, the CD4+ cells from As-BD patients were less susceptible to arsenic-induced apoptosis, due to reduced tumor necrosis factor receptor 1 expression. Interestingly, arsenic was found to induce Fas expression on CD4+ cells and increase the soluble Fas ligand (sFasL) production from keratinocytes. This sFasL-containing keratinocyte supernatant was able to induce comparable CD4+ cell apoptosis for both patients and controls. Using immunofluorescent staining, increased FasL was observed in keratinocytes of As-BD lesions and Fas was expressed among infiltrating CD4+ cells. Our findings suggested that systemically, the percentage of CD4+ cells was decreased in the peripheral blood of As-BD patients. These residual CD4+ cells were less susceptible to arsenic-induced apoptosis. However, once infiltrated into the As-BD lesions, the selective CD4+ cell apoptosis might be mediated by FasL from keratinocytes. This additional tumor-anti-immune phenomenon present in the cutaneous environment provides a reasonable explanation for frequent occurrence of arsenic cancers in the skin.
Abbreviations: AP-1, activator protein 1; As-BD, arsenic-induced Bowen's disease; BD, Bowen's disease; FITC, fluorescein isothiocyanate; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; PE, phycoerythrin; sFasL, soluble Fas ligand; TNF, tumor necrosis factor; TNF-R1, tumor necrosis factor receptor 1; TRADD, tumor necrosis factor receptor-associated death domain
Received February 9, 2009; revised March 30, 2009; accepted April 12, 2009.