Carcinogenesis Advance Access first published online on April 17, 2009
This version published online on April 25, 2009
Carcinogenesis, 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 Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
2 Department of Internal Medicine and Institute of Molecular Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
3 Department of Dermatology, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Clinical Pathology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
5 Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Corresponding author: Hsin-Su Yu, MD., PhD., Department of Dermatology, Kaohsiung Medical University, NO. 100 Shih Chuan 1st Road, Kaohsiung, Taiwan 807. TEL: 886-7-3117820 FAX: 886-7-3212062 E-mail: 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 BD (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 to control subjects. However, the CD4+ cells from As-BD patients were less susceptible to arsenic-induced apoptosis, due to reduced TNF-R1 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 immunoflourescent 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.
Key Words: Arsenic • Bowen's disease • Apoptosis • CD4+ cells
Author Forename and Surname corrected for Cheng-Che E. Lan
Received February 9, 2009; revised March 30, 2009; accepted April 12, 2009.