Aberrant immune responses in arsenical skin cancers.
ABSTRACT Arsenic is a well-known human carcinogen. It also impairs immune functions and activation in many aspects. However, only a small portion of arsenic-exposed population develops skin abnormalities, including Bowen's disease and skin cancers. Differential immune activation among the individuals might account for the different susceptibilities. In patients with arsenic-induced Bowen's disease, there is a selective CD4 T-cell apoptosis through tumor necrosis factor-alpha pathway, decrease in macrophage differentiation and phagocytosis, reduced Langerhans cell numbers and dendrites, altered regulatory T-cell distribution, and other immune alterations. Several lines of evidence from mouse and fish studies also confirmed the potent and multifaceted effects of arsenic in the immune system. The molecular bases of immunosuppression by arsenic in lymphocytes may include chromosomal and DNA abnormalities, decreased T-cell receptor activation, and the cellular status of oxidation and methylation. This article also reviews the causative and differential role of selective CD4 cell apoptosis and the carcinogenesis of arsenic-induced Bowen's disease.
- SourceAvailable from: Yau-Huei Wei[show abstract] [hide abstract]
ABSTRACT: The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases.International Journal of Molecular Sciences 01/2013; 14(3):6414-35. · 2.46 Impact Factor