Review
Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis

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Abstract

Ultraviolet (UV) radiation causes inflammation, gene mutation and immunosuppression in the skin. These biological changes are responsible for photocarcinogenesis. UV radiation in sunlight is divided into two wavebands, UVB and UVA, both of which contribute to these biological changes, and therefore probably to skin cancer in humans and animal models. Oxidative damage caused by UV contributes to inflammation, gene mutation and immunosuppression. This article reviews evidence for the hypothesis that UV oxidative damage to these processes contributes to photocarcinogenesis. UVA makes a larger impact on oxidative stress in the skin than UVB by inducing reactive oxygen and nitrogen species which damage DNA, protein and lipids and which also lead to NAD+ depletion, and therefore energy loss from the cell. Lipid peroxidation induces prostaglandin production that in association with UV-induced nitric oxide production causes inflammation. Inflammation drives benign human solar keratosis (SK) to undergo malignant conversion into squamous cell carcinoma (SCC) probably because the inflammatory cells produce reactive oxygen species, thus increasing oxidative damage to DNA and the immune system. Reactive oxygen or nitrogen appears to cause the increase in mutational burden as SK progress into SCC in humans. UVA is particularly important in causing immunosuppression in both humans and mice, and UV lipid peroxidation induced prostaglandin production and UV activation of nitric oxide synthase is important mediators of this event. Other immunosuppressive events are likely to be initiated by UV oxidative stress. Antioxidants have also been shown to reduce photocarcinogenesis. While most of this evidence comes from studies in mice, there is supporting evidence in humans that UV-induced oxidative damage contributes to inflammation, gene mutation and immunosuppression. Available evidence implicates oxidative damage as an important contributor to sunlight-induced carcinogenesis in humans.

Introduction

Ultraviolet (UV) radiation that reaches the surface of the Earth from the sun is divided into two wavebands, UVB (290–320 nm) and UVA (320–400 nm), with visible light being at longer wavelengths. UV can cause direct biological damage, or indirect damage via the production of reactive oxygen species (ROS). ROS cause oxidative damage to DNA, proteins and lipids. Whereas UVB and UVA both cause oxidative damage, UVA is generally regarded to cause a large amount of its deleterious effects via this mechanism, whereas UVB is generally regarded to mainly cause direct damage. UVA induction of ROS is important for at least some of the biological effects of this waveband [1].

UV radiation increases the activity of xanthine oxidase in human keratinocytes, increasing production of superoxide [2]. Additionally there are a variety of chromophores, such as porphyrins and heme in human skin, which could produce ROS in response to UVA radiation; however, these remain poorly defined [3], [4], [5]. UVA produces a variety of ROS in the skin, including superoxide and hydrogen peroxide (Fig. 1). All of these are likely to contribute to the damaging biological effects of UVA on DNA, lipids and proteins [3]. The epidermis contains antioxidant defenses including the enzymes, superoxide dismutase, glutathione peroxidase and catalase, which remove ROS from the skin [6]. Free radical scavengers, such as Vitamins C and E, carotenoids and glutathione are also present in the skin to reduce the damaging effects of ROS. Increased production of ROS following exposure to UV can deplete these antioxidant defences, leaving the skin vulnerable to attack from ROS [7].

Nitric oxide (NO) is produced by a family of inducible, neural and endothelial NO synthase (iNOS, nNOS and eNOS, respectively) from l-arginine. Both UVA and UVB activate NOS in the skin, increasing levels of NO [8], [9]. NO, produced by UV upregulated nitric oxide synthase can combine with UV-induced superoxide to form peroxynitrite that exists in equilibrium with peroxynitrous acid. These reactive nitrogen species are very toxic, and can cause DNA damage, nitrosylation of tyrosine residues in proteins, and initiate lipid peroxidation, all of which interfere with cellular function.

Poly(ADP-ribose) polymerase (PARP) is activated in response to DNA damage caused by peroxynitrite. It breaks down NAD+ into nicotinamide and ADP-ribose, leading to a shortage of this molecule in skin cells, which in turn reduces ATP formation. The ensuing low energy level disrupts cell function, and in extreme cases cell death ensues [10]. UV radiation has been shown to reduce NAD+ levels in the skin [11]. Thus, another consequence of UV-induced NO and superoxide production is peroxynitrite leading to cellular energy loss.

Inflammatory cells, such as macrophages and neutrophils, also produce large amounts of ROS and NO resulting in peroxynitrite formation, DNA damage NAD+ depletion and energy loss from cells [12], [13], [14]. This is likely to be an important mechanism of damage to tissues and cells being targeted by the inflammatory cells. These events are similar in many ways to UVA-induced oxidative damage. As sunlight causes inflammation, oxidative damage could occur either as a direct response to the UVA or indirectly from inflammatory cells activated in response to the sunlight.

UV radiation has many biological effects on the skin that contribute to photocarcinogenesis. Low-level exposure increases synthesis of Vitamin D, which protects from genetic damage and carcinogenesis [15]. High-level exposure causes formation of sunburn cells, which are cells dying of apoptosis. This protects from photocarcinogenesis, as dead cells do not form cancers. At doses in between these UV suppresses immunity and leads to gene mutation. UV also promotes inflammation. These three biological events cause skin cancer. Thus, this review on UV-induced oxidative stress in inflammation, gene mutation and photoimmunosuppression will concentrate on the connection between these events and photocarcinogenesis. An emphasis is given to evidence from whole animal and human studies.

Section snippets

The connection between UV-induced oxidative stress, inflammation and carcinogenesis

UV augments blood flow and infiltration by blood leukocytes, such as macrophages and neutrophils into the skin, observed clinically as inflammation. Increased production of NO and prostaglandins contribute to these events [16], [17]. UV radiation-induced lipid peroxidation increases production of prostaglandins (PG), including PGE2, which in turn cause inflammation in the skin [18]. PGE2 is produced from arachidonic acid by the inducible form of cyclooxygenase (COX), COX-2. This is thought to

UV-induced oxidative damage and gene mutation

There is little direct evidence for oxidative damage to DNA making a substantial contribution to photocarcinogenesis. The formation of micronuclei is an indication of chromosomal rearrangement or genetic instability. UVA-induced micronucleus formation in cultured HaCa T cells was reduced by treatment with catalase suggesting a role for hydrogen peroxide in this form of UVA-induced genetic damage [47].

UVB absorbed by two adjacent cytosine (C) residues in DNA causes the formation of cyclobutane

UV-induced oxidative stress and photoimmunosuppression

Both UVB and UVA suppress the immune system of humans and mice. UVB-induces immunosuppression by events downstream from DNA absorption forming pyrimidine dimers [58] or trans urocanic acid absorption of UVB, so that it isomerises to the immunosuppressive cis form [59], [60]. UVA is also immunosuppressive in both humans [61], [62] and mice [63], [64]. A number of studies have shown that to prevent immunosuppression in response to solar-simulated UV radiation (containing a mixture of UVB and UVA

Antioxidants reduce skin carcinogenesis

Finally, antioxidants have been shown to reduce photocarcinogenesis, and whereas it is not always clear whether they mediated this effect by preventing inflammation, gene mutation or immunosuppression, they show that reactive oxygen or nitrogen is important for photocarcinogenesis. The antioxidant Vitamin E delays or reduces UV radiation-induced skin carcinogenesis in mice, through a reduction in DNA damage, immunosuppression or both [82], [92], [93]. Addition of inhibitors of NO or ROS

Conclusions

Available evidence indicates that UV-induced oxidative stress is important in skin cancer development. Whereas sufficient evidence exists in animal models and humans to support this, many details are not yet known and further research is required in this area. UV radiation in sunlight, particularly the UVA waveband, at physiological doses to which humans are readily exposed is able to produce a range of oxidative stress responses in the skin. These include the production of a variety of

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