Solar ultraviolet radiation as a trigger of cell signal transduction

Abstract

Ultraviolet light radiation in sunlight is known to cause major alterations in growth and differentiation patterns of exposed human tissues. The specific effects depend on the wavelengths and doses of the light, and the nature of the exposed tissue. Both growth inhibition and proliferation are observed, as well as inflammation and immune suppression. Whereas in the clinical setting, these responses may be beneficial, for example, in the treatment of psoriasis and atopic dermatitis, as an environmental toxicant, ultraviolet light can induce significant tissue damage. Thus, in the eye, ultraviolet light causes cataracts, while in the skin, it induces premature aging and the development of cancer. Although ultraviolet light can damage many tissue components including membrane phospholipids, proteins, and nucleic acids, it is now recognized that many of its cellular effects are due to alterations in growth factor- and cytokine-mediated signal transduction pathways leading to aberrant gene expression. It is generally thought that reactive oxygen intermediates are mediators of some of the damage induced by ultraviolet light. Generated when ultraviolet light is absorbed by endogenous photosensitizers in the presence of molecular oxygen, reactive oxygen intermediates and their metabolites induce damage by reacting with cellular electrophiles, some of which can directly initiate cell signaling processes. In an additional layer of complexity, ultraviolet light-damaged nucleic acids initiate signaling during the activation of repair processes. Thus, mechanisms by which solar ultraviolet radiation triggers cell signal transduction are multifactorial. The present review summarizes some of the mechanisms by which ultraviolet light alters signaling pathways as well as the genes important in the beneficial and toxic effects of ultraviolet light.

Introduction

With the recognition that ultraviolet light is a major causative factor in the development of human skin cancer, a surge of interest has arisen on understanding its mechanism of action in sun-exposed tissues. Acting as both a tumor initiator and a tumor promoter, ultraviolet light is one of the best-characterized environmental carcinogens (Cadet et al., 2001). It is also a potent modulator of cell growth and differentiation, and some of its actions are important in normal physiological activity in the skin, for example, induction of melanogenesis. In some cases, the physiological responses of the skin to ultraviolet light are therapeutic and significant improvements have been observed in patients with epidermal proliferative disorders such as psoriasis and atopic dermatitis. In excessive amounts, however, ultraviolet light can exert toxicity. Responses of the skin to ultraviolet light are dependent on many variables including wavelength, dose and characteristics of the skin tissue, and range from mild inflammation and erythema to hyperplasia, burns, aging, and cutaneous malignancies. Individual genetic susceptibility is an important determinant of responsiveness to ultraviolet light. For example, recent studies have shown that ultraviolet light resistant individuals possess unique genetic polymorphisms in genes encoding the cytokine interleukin-1β (Sleijffers et al., 2003), an important regulator of skin inflammation. In addition, certain genetic polymorphisms in the tumor necrosis factor α (TNF-α)¹ gene have been shown to confer susceptibility to ultraviolet-induced suppression of contact hypersensitivity responses Niizeki et al., 2002, Niizeki et al., 2001, Vincek et al., 1993. Skin exposure to ultraviolet light also induces systemic effects including suppression of both specific and nonspecific immune responses (Hurks et al., 1994). These responses may contribute to the overall toxic or therapeutic effects of ultraviolet light and may be important in the resolution of inflammation and wound healing.

It is generally thought that UVB irradiation (ultraviolet radiation in wavelengths from 280 to 320 nm) and to a much lesser extent UVA (ultraviolet light in wavelengths from 320 to 400 nm) are responsible for sunlight-induced cancers Cole et al., 1986, de Gruijl et al., 1993. Presumably, the carcinogenic process is initiated by DNA damage (Ichihashi et al., 2003). In the case of UVB light, DNA damage occurs by the direct formation of pyrimidine (6–4) pyrimidone photodimers (6–4 photoproducts) and cyclobutane pyrimidine dimers (thymine dimers), as well as through the formation of reactive oxygen species (Ravanat et al., 2001). With UVA light, bipyrimidine photoproducts rather than oxidative lesions appear to be responsible for DNA damage (Douki et al., 2003). It is well known that by virtue of the need to maintain genetic integrity of nucleic acids, DNA damage by itself can trigger cellular responses to ultraviolet light including activation of DNA repair and cell cycle control enzymes, and this is an important process contributing to many of the biological effects of sunlight (Goodman, 2002). However, it is becoming increasingly apparent that these biological effects can occur as a consequence of ultraviolet light-induced signaling events in distinct epidermal cell populations leading to changes in patterns of gene expression that control the various physiological and structural changes observed in the skin.

Global changes in expression of ultraviolet light modulated genes have been observed at the mRNA level using a variety of techniques including microarrays, cDNA library screening, and differential display Abts et al., 1997, Abts et al., 2000, Dazard et al., 2003, Murakami et al., 2001, Nolan et al., 2003, Rosen et al., 1995, Sesto et al., 2002, Takao et al., 2002, and by protein analysis using two dimensional gel electrophoresis Maytin, 1992, Molloy and Laskin, 1987, Molloy and Laskin, 1988, Molloy and Laskin, 1992, Molloy et al., 1987. Changes in expression of many specific genes have also been characterized including those regulating inflammation, cell growth and differentiation, oncogenesis, and signal transduction. Ultraviolet light can both decrease and increase expression of genes in skin cells. For example, UVB light has been reported to down-regulate the chemokine receptor CXCR-2 (Kondo et al., 2000), the mRNA nuclear export gene product XPO1, topoisomerase II-binding protein, and differentiation-dependent A4 protein (Potter et al., 2000), the anti-apoptotic protein Bcl-2 Isoherranen et al., 1999a, Isoherranen et al., 1999b, connective tissue growth factor Quan et al., 2002a, Quan et al., 2002b, transforming growth factor-β (TGF-β) type II receptor (Quan et al., 2001), and the keratinocyte growth factor receptor (KGFR) (Finch et al., 1997), but to up-regulate expression of p21(WAF1/CIP1) (Lu et al., 1999), p53 (Ponten et al., 2001), c-jun and c-fos (Soriani et al., 2000), the early growth response-1 gene (Huang et al., 1999), ornithine decarboxylase (Rosen et al., 1990), urokinase type plasminogen activator receptor (Marschall et al., 1999), intercellular adhesion molecule (ICAM-1) (Cornelius et al., 1994), matrix metalloproteinase-8 (Fisher et al., 2001), thioredoxin (Sachi et al., 1995), TGF-β (Lee et al., 1997), cyclooxygenase-2 (COX-2) Isoherranen et al., 1999a, Isoherranen et al., 1999b, TNF-α Köck et al., 1990, Pupe et al., 2003, interleukin-1 (IL-1) (Kondo et al., 1994), interleukin-6 (IL-6) (Urbanski et al., 1990), interleukin-8 (IL-8) (Kondo et al., 1993), and interleukin-10 (IL-10) (Enk et al., 1995). Ultraviolet light also modulates the expression of TGF-β transcripts as well as mRNA for the Smad proteins that mediate TGF-β signaling Quan et al., 2002a, Quan et al., 2002b. UVB light can also interfere with the ability of cytokines and growth factors to modulate gene expression. In this regard, Sur et al. (2002) have shown that UVB light is a potent inhibitor of γ-interferon-induced inducible nitric oxide synthase in murine keratinocytes and macrophages.