Differential effects of arsenic on cutaneous and systemic immunity: focusing on CD4+ cell apoptosis in patients with arsenic-induced Bowen's disease.
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.
Liao
Wei-Ting
WT
Graduate Institute of Medicine, Kaohsiung Medical University, Taiwan, Republic of China.
Yu
Chia-Li
CL
Lan
Cheng-Che E
CC
Lee
Chih-Hung
CH
Chang
Chung-Hsing
CH
Chang
Louis W
LW
You
Huey-Ling
HL
Yu
Hsin-Su
HS
D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000633:toxicity*; D001913:Bowen's Disease / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D007110:Immunity, Active / Q000187:drug effects; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology
D053222:Fas Ligand Protein; D001151:Arsenic