Influence of wind on chronic ultraviolet light-induced carcinogenesis

Wind enhances the carcinogenic effect of chronic ultraviolet radiation (UVL). This was demonstrated in hairless mice that were irradiated for 42 weeks with mercury are lamps. One group of animals was exposed to continuous wind flow of 2.7 m/s except for the daily 1-2 min time interval when they were removed from the wind tunnel and irradiated. Another group of animals received identical irradiation but were protected from wind. The first tumour appeared in the UVL and wind group after 105 days of irradiation, and at 164 days of irradiation all surviving mice in the group had developed tumours. The group of mice receiving identical irradiation but protected from wind had their first tumour appear at 154 days of irradiation, and by 164 days of irradiation only 40% of the mice had developed tumours.     

Polypodium leucotomos inhibits ultraviolet B radiation-induced immunosuppression

Background: An extract of the tropical fern Polypodium leucotomos (PL) administered orally to mice inhibits ultraviolet B (UVB) radiation-induced skin cancer formation. UVB-induced murine skin cancers occur, in part, because of UVB-induced immunosuppression. Thus, we examined whether PL inhibits UVB-suppression of the induction of contact hypersensitivity (CHS) locally or systemically.
Methods: C57BL/6 mice received standard drinking water or water-containing PL. In the local model, mice were shaved on the dorsum and exposed to 3500 J/m² of UVB radiation daily for 4 days. Control mice were not irradiated. After the last irradiation they were sensitized to oxazolone topically at the irradiated site. To examine the ability of PL to inhibit systemic UVB-induced immunosuppression, mice were given 10 000 J/m² of UVB radiation once and immunized at a non-exposed site 3 days later. Six days after immunization (in both models), mice were challenged on the ears with oxazolone and 24/48 h ear swelling assessed.
Results: PL in drinking water significantly reduced the inhibition of CHS observed with exposure to UVB radiation in both the local and systemic models.
Conclusions: The ability of PL to inhibit UVB radiation-induced immune suppression may explain, in part, its ability to inhibit UVR-induced skin cancer induction in mice.     

An action spectrum for ultraviolet radiation-induced immunosuppression in humans

Background The immune‐suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear. Objectives We previously determined wavelength dependencies for immunosuppression by UVB and UVA wavebands in humans. We now aimed to calculate relative and solar immune‐suppressive effectiveness across the UVB and UVA spectra. Methods We used the nickel model of recall contact hypersensitivity to determine UV immunosuppression dose responses and minimum immune suppression doses (MISDs) at 11 narrowbands from 289 to 392 nm. The relative immune‐suppressive effectiveness of each narrowband was then determined as 1/MISD vs. wavelength. This curve was multiplied by the solar spectrum to show the relative immune‐suppressive effectiveness of each waveband in sunlight. Results We found peaks of immune‐suppressive effectiveness in the UVB waveband at 300 nm and in the UVA at 370 nm. Because of the far greater amount of longwave UVA in sunlight, the relative solar immune‐suppressive effectiveness of UVA was threefold higher than that of UVB at doses equivalent to sun exposure from normal daily activities. Conclusions Longwave UVA, which abuts the visible light spectrum and is less effectively filtered by sunscreens than UVB, is likely to be the largest contributor to immunosuppression resulting from incidental daily sun exposure.     

Dietary lutein reduces ultraviolet radiation-induced inflammation and immunosuppression

Ultraviolet radiation (UVR) promotes skin cancer development by mutagenic, immunosuppressive, and oxidative-stress-inducing mechanisms; however, certain antioxidants may counteract and prevent UVR-induced photodamage. Lutein is a xanthophyll carotenoid with potent antioxidant activity. Because reactive oxygen species (ROS) are believed to have a role in UVR-induced skin damage, we investigated whether lutein can modify UVR effects including the tissue swelling response to midrange UVR (280-320 nm, ultraviolet B (UVB) radiation) and UVB suppression of contact hypersensitivity (CHS) in both the local and the systemic models of UV-induced immunosuppression. We found that compared to mice fed the standard laboratory diet, mice fed dietary lutein demonstrated significant inhibition of ear swelling owing to UVB radiation. Mice exposed to 1700 J per m2 UVB radiation four times at daily intervals and then sensitized to dinitrofluorobenzene at the site of irradiation showed a decreased CHS response upon challenge. This suppression by UVB radiation was significantly inhibited by lutein feeding. When UVB radiation was given at a single dose of 10,000 J per m2 to inhibit the induction of CHS at a distant, nonirradiated site, no effect of lutein was seen. Finally, lutein accumulated in the skin of mice following diet supplementation and was shown to decrease ROS generation following UVR exposure. Thus, lutein modulates the skin's response to UVR and may contribute to the defense against some of the deleterious effects of solar radiation.     

Age dependence of ultraviolet light-induced erythema following narrow-band UVB exposure

BACKGROUND/PURPOSE: A report in the literature suggests longer duration and greater intensity of late phase UVB erythema in older people. The aim of this study was to identify differences in minimum erythema dose (MED) and intensity of UV-induced erythema after narrow band UVB exposure between older and younger individuals in the late phase of UVB erythema. METHODS: Using the UVA/TL 01 UV skin tester (Waldmann Medizintechnik, Villingen-Schwenningen, Germany), MED was determined for narrow-band UVB exposure in 20 young subjects aging from 20-40, and 20 elderly subjects over 70 years of age. The intensity of UV-induced erythema was measured by chromametry (a*-value and L-value) and laser Doppler 48 h after irradiation. Minimum erythema dose (MED) was additionally assessed visually. RESULTS: Elderly subjects showed no statistical different MED compared to younger subjects. However, the erythema intensity 48 h after narrow-band UVB exposure was significantly greater in the elderly. CONCLUSIONS: Narrow-band UVB therapy may, in case of over dosage, produce more intense erythema in the late phase of UVB erythema in old people than in younger individuals.     

Suppression of ultraviolet light-induced tumor formation by dietary antioxidants.

Dietary antioxidants were effective in reducing the number and severity of ultraviolet light-induced squamous cell carcinomas in skin of hairless mice. This and previous studies suggest that antioxidants may play a role in both inhibition of the primary event(s) involved in ultraviolet light-mediated tumor induction and the subsequent development of precancerous lesions into tumors.     

Squalene peroxides may contribute to ultraviolet light-induced immunological effects.

Ultraviolet (UV) irradiation is capable of producing a dose-dependent decomposition of skin surface lipids and particularly of squalene, with the concomitant generation of active lipoperoxides. The biological effects of UV-peroxidated squalene were tested, compared with those produced by synthetic lipoperoxides (cumene hydroperoxide), on some immunological parameters in vivo modified by UVB irradiation. Application of UV-peroxidated squalene as well as cumene hydroperoxide significantly inhibited the induction of contact hypersensitivity to dinitrofluorobenzene in mice, which was associated with a decrease in the number of ATPase positive cells. The effect was dose-dependent (over 40 micrograms for peroxidated squalene and over 20 micrograms for cumene) and relevant after 2 d of treatment. Down-regulation towards the applied hapten was demonstrated. The results indicate that UV-induced lipoperoxides of squalene are capable of inhibiting the induction of contact hypersensitivity in mice and suggest that, among the other photoproducts generated in humans, squalene peroxides may play a role as biochemical messengers of the biological effects of UV irradiation of the skin.     

Topical riboflavin attenuates ultraviolet B‐ and ultraviolet A‐induced immunosuppression in humans

Background: Riboflavin (vitamin B₂) plays a key role in cellular energy metabolism. We have observed previously that nicotinamide (vitamin B₃), which is also centrally involved in cellular energy restoration after UV irradiation, is highly immune protective in humans. We thus hypothesized that riboflavin might also confer immune protection. Methods: We irradiated healthy, nickel‐allergic volunteers with narrowband UVA (385 nm) and UVB (300 nm) at separate sites on the lower back. These areas were treated with riboflavin solution or vehicle at 24 h and again at 30 min before UV exposure. Forty‐eight hours after irradiation, volunteers were patch tested with nickel‐containing Finn chambers, at both irradiated and nonirradiated sites, with and without prior riboflavin treatment. The resulting contact hypersensitivity reactions at each site were then measured 72 h later with a reflectance erythema meter in order to determine and compare the immune suppressive effects of each intervention. Results: We observed that low doses of both UVB and longwave UVA1 were immune suppressive in humans. Topical riboflavin conferred immune protection against both wavebands. Conclusions: Riboflavin is immune protective in humans, and this may reflect the role of the B group vitamins in cellular energy restoration after UV exposure.     

The activity of interferon on ultraviolet light-induced squamous cell carcinomas in mice

The activity of interferons was tested in ultraviolet light-induced skin tumors in mice. After the tumors were well established, they were injected and measured daily for 19 days. Mouse virus type (IF-alpha + IF-beta) and immune (IF-gamma) interferons were injected intralesionally into three groups of test animals and compared with a fourth group which received mock interferon (control). When used separately, virus type and immune interferons did not affect tumor growth; however, we observed regression in tumor size when the two interferons were used in combination.     

树突细胞在UV诱导皮肤免疫抑制中的作用

局部免疫抑制经iC3b-Mo/Mph-丝裂原活化蛋白激酶信号传导途径,诱导细胞外信号调节激酶p44/42磷酸化,产生高水平的IL-10,促进单核巨噬细胞朝巨噬细胞的方向发展,以吞噬UV暴露部位的坏死细胞.同时抑制磷酸化p38丝裂原活化蛋白激酶和IL-12的产生,阻碍单核巨噬细胞向CDlc+树突细胞方向分化和成熟,以抑制T细胞主导的免疫反应.在UV引起的系统性免疫抑制中,其机制并非通过直接抑制DC的数量和功能,而是通过引流淋巴结中活化B细胞抑制DC所诱导的Th1免疫反应得以实现.     

A long-term time course of colorimetric evaluation of ultraviolet light-induced skin reactions

Many attempts have been made to quantify ultraviolet (UV) radiation-induced erythema and pigmentation. However, most of these studies were concerned with the early changes of reactions and neglected events occurring in later stages. The long-term course of skin colour changes in pigmented skin, induced by broad band UVA and UVB radiation, was evaluated in 30 Korean male volunteers by means of a tri-stimulus colorimeter for 10 weeks. The L*a*b* system recommended by the Commission International de l'Eclairage was used to measure skin colour. The L* value (luminance) gives the relative lightness ranging from total black to total white. The a* value represents the balance between red and green and the b* value the balance between yellow and blue. The mean individual typology angle of our subjects was 47.3 degrees, indicating 'light' group of constitutional skin colour category. One day after UV exposure, the L* and b* values decreased significantly, following the colour direction of persistent pigment darkening. They then changed in opposite directions persistently until week 1, when maximum tanning was obtained. Then, a shift toward the original values was observed parallel to the constitutive melanization axis. The a* index showed a significant increase toward the mean colour of haemoglobin on day 1. It returned to its original value following the pathway of constitutive melanization axis. This promising quantitative method may enable objective measurement of dermatophysiologic changes to be made, and allow evaluation of the efficacy of therapeutic modalities on skin disorders without the inherent errors associated with subjective judgement. Our results would provide standard data for long-term UV-induced skin erythema and pigmentation.     

Mechanisms of local, low-dose UVB-induced immunosuppression in contact hypersensitivity.

Preirradiation of contact sensitizing sites to low-dose ultraviolet B (UVB) renders animals unresponsive to challenge reaction. This unresponsiveness is known as local, low-dose UVB-induced immunosuppression. Although researchers in this area have developed theories, the exact mechanisms of UVB-induced immunosuppression are still a matter of controversy. This article reviewed various scientific data on UVB-induced immunosuppression, categorizing them into individual sequential steps in the whole cascade.     

Suppressive effect of recombinant human thioredoxin on ultraviolet light-induced inflammation and apoptosis in murine skin

Thioredoxin (TRX) is a small ubiquitous protein, which regulates cellular redox status and scavenges reactive oxygen species. The present study was conducted to investigate the effect of TRX on ultraviolet (UV)-B-mediated inflammatory and apoptotic responses. Ear swelling after UV-B irradiation was significantly reduced in TRX-transgenic mice compared to wild-type mice. Administration i.p. of recombinant human TRX also reduced acute skin inflammatory reaction, such as skin erythema and swelling. Histologically, numbers of inflammatory cells including neutrophils and lymphocytes were significantly reduced and the average size of the caliber of blood vessels were also reduced in recombinant human TRX-injected mice. The number of apoptotic keratinocytes, in terms of sunburn cells, activated-caspase-3-positive cells and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were all significantly reduced in recombinant human TRX-injected mice. Immunohistochemical intensity of 8-hydroxy-2'-deoxyguanosine was strikingly reduced in recombinant human TRX-injected mouse. Western blotting showed that administration of recombinant human TRX attenuated duration of phosphorylation of p38 mitogen-activated protein kinases and intensity of phosphorylation of c-Jun N-terminal kinase in the early phase, which play important roles in inflammatory and apoptotic signaling. Collectively, these findings indicated that recombinant human TRX attenuated inflammatory and apoptotic responses caused by UV-B. Possible mechanisms for this might be via redox regulation of stress signaling and reduction of reactive oxygen species.     

Green tea polyphenols prevent ultraviolet light-induced oxidative damage and matrix metalloproteinases expression in mouse skin

Chronic exposure of solar ultraviolet (UV) light to human skin results in photoaging. UV-induced oxidative damage and induction of matrix metalloproteinases (MMP) have been implicated in this process. Because polyphenols from green tea (GTP) prevent other cutaneous adverse effects of UV radiation we hypothesized that UV irradiation-induced oxidative damage and induction of MMP might be prevented in vivo in mouse skin by oral administration of GTP. GTP was administered in drinking water (0.2%, wt/vol) to SKH-1 hairless mice, which were then exposed to multiple doses of UVB (90 mJ per cm2, for 2 mo on alternate days) following in vivo photoaging animal protocol. Treatment of GTP resulted in inhibition of UVB-induced protein oxidation in vivo in mouse skin, a hallmark of photoaging, when analyzed biochemically, by immunoblotting, and immunohistochemistry. GTP treatment also inhibited UVB-induced protein oxidation in vitro in human skin fibroblast HS68 cells, which supports in vivo observations. Moreover, oral administration of GTP also resulted in inhibition of UVB-induced expression of matrix degrading MMP, such as MMP-2 (67%), MMP-3 (63%), MMP-7 (62%), and MMP-9 (60%) in hairless mouse skin. These data suggest that GTP as a dietary supplement could be useful to attenuate solar UVB light-induced premature skin aging.     

Nitric oxide appears to be a mediator of solar-simulated ultraviolet radiation-induced immunosuppression in humans

Topical application of NG-methyl-L-arginine and 2,2'-dipyridyl were used to examine the respective roles of nitric oxide and reactive oxygen species in solar-simulated ultraviolet radiation-induced immunosuppression in humans in vivo. Immunosuppression was studied using a nickel contact hypersensitivity recall model. Ultraviolet radiation dose-responses were generated to determine the extent to which NG-methyl-L-arginine and 2,2'-dipyridyl affected the immune response. NG-methyl-L-arginine but not 2,2'-dipyridyl protected the immune system from ultraviolet radiation-induced suppression. Both NG-methyl-L-arginine and 2,2'-dipyridyl inhibited nitrite production. Nitrite is a degradation product of peroxynitrite, a cytotoxic mediator resulting from reactions between nitric oxide and reactive oxygen species. This suggests that nitric oxide, not its downstream product peroxynitrite, was likely to be responsible for solar-simulated ultraviolet radiation-induced immunosuppression. In contrast, both nitric oxide and reactive oxygen species were mediators of solar-simulated ultraviolet radiation-induced apoptosis and loss of dendritic S-100+ cells (probably Langerhans cells) from the epidermis. It is likely that different mechanisms are involved in these ultraviolet-induced endpoints and that events in addition to Langerhans cell depletion are important for local immune suppression to recall antigens in humans. Understanding the mechanisms of cutaneous ultraviolet-induced oxidative stress will assist in the future design of novel products that protect skin from photoaging and skin cancer.     

Oxygen intermediates are involved in ultraviolet radiation-induced damage of Langerhans cells

Experiments were conducted to determine whether ultraviolet (UV) radiation exerts its effect through the generation of oxygen intermediates on Langerhans cells (LC). Guinea pigs were exposed to one single dose of UVB (0.9-2.7J/cm2), and biopsy specimens were taken 5 days after the irradiation. The population of LC was evaluated using ATPase-stained epidermal sheets. These exposures reduced the number of LC to 20-25% of the original density. On the other hand, superoxide dismutase (SOD) (0.02-0.2 mg), a scavenger of superoxide anion, which had been injected intradermally just before UV radiation, significantly prevented the depletion of LC, although not completely (37-40% of the original density). The injection immediately after the exposure was still significantly effective, but less so. Other scavengers of oxygen intermediates including catalase, D-mannitol, and L-histidine revealed no detectable effect. A single exposure of UVB at doses of 0.3-0.6 J/cm2 did not deplete the ATPase-positive LC. However, the same dose of UVB reduced the number of LC to 70%, when exposed after the injection of an SOD inactivator, diethyldithiocarbamate, possibly due to inactivation of physiologically existing SOD. These observations indicate that oxygen intermediates such as superoxide anion or its subsequent species are generated by UV radiation exposure and damage the epidermal LC.     

Histamine is involved in ultraviolet B-induced pigmentation of guinea pig skin

We previously reported that histamine induced melanogenesis in cultured human melanocytes and that the stimulatory effect was mediated by protein kinase A activation via H2 receptors. It is well-known that ultraviolet B irradiation causes acute inflammation, known as erythema, and subsequent pigmentation, and there are several reports demonstrating an elevation of the histamine levels in ultraviolet B-irradiated skin. Thus, to evaluate the involvement of histamine in ultraviolet B-induced skin pigmentation, we examined the effect of an H2 antagonist in brownish guinea pig skin. Daily exposure to 200 mJ per cm2 ultraviolet B for 3 d evoked erythema and subsequent pigmentation in the skin samples tested. Moreover, a remarkable increase in dopa-positive melanocytes was observed in the pigmented area, which showed an increase in melanin synthesis. Topical application of famotidine, an H2 antagonist, significantly reduced pigmentation and moderated the increase of dopa-positive melanocytes in the ultraviolet B-irradiated skin. Even when the initiation of famotidine application was delayed to day 2 after irradiation, an inhibitory activity on ultraviolet B-induced pigmentation was observed; however, the ultraviolet B-induced erythema was not suppressed by topically applied famotidine. Thus, we concluded that histamine is involved in ultraviolet B-induced pigmentation and that famotidine suppressed the pigmentation by the prevention of histamine binding to H2 receptors in melanocytes but not by prevention of ultraviolet B permeability and inflammation.