Topic Article:
UV Radiation-Induced Immunosuppression Is Greater in Men and Prevented by Topical Nicotinamide
Diona L. Damian, Clare R.S. Patterson, Michael Stapelberg, Joohong Park, Ross St.C. Barnetson and Gary M Halliday
Journal of Investigative Dermatology (2008) 128, 447–454; doi:10.1038/sj.jid.5701058

Topical Nicotinamide Prevents UV Immunosuppression

Nancy Kim^1^, Aparche Yang^1^ and Robert S. Kirsner^1^

Journal of Investigative Dermatology (2008) 128, 250; doi:10.1038/sj.jid.5701230

UV light is a major risk factor for skin cancer development (Essen and Klar, 2006). The mechanisms by which UV leads to cancer formation are complex and appear not to be limited solely to UV-induced DNA damage. UV induces immune suppression, which is associated with increased skin cancer formation, as evidenced by the increased cancer risk in immunosuppressed transplant patients (Bergstresser, 1983; Ulrich and Stockfleth, 2007). Therefore, protection against UV-induced immune suppression may have clinical benefits.

Damian et al. (2008) explore the potential role of topical nicotinamide in preventing UV immunosuppression in humans, based on animal models to prevent UV-induced immune suppression. Using volunteers with a positive Mantoux test (purified protein derivative positive from Bacille Calmette-Guérin vaccination), the authors studied the ability of topical nicotinamide to prevent UVB immune suppression and the mechanisms by which this occurred. They found that when nicotinamide was applied either before or after UV exposure (simulating normal sunlight exposure), the typically encountered immune suppression was reduced. Additionally, men were more sensitive to UV-light-induced immune suppression, which the investigators concluded may account, in part, for the greater incidence of skin cancer and skin cancer mortality in men. Nicotinamide did not work as a sunscreen but rather, as suggested by microarray analysis, as a mechanism that may include alterations in complement, energy metabolism, and apoptosis.

Through the following questions we will delve into this paper in greater detail.

QUESTIONS

1. What are the major findings of the study?

2. Why is UV-induced immunosuppression important to cancer development?

3. Were the UV doses given in this study appropriate?

4. Is nicotinamide a sunscreen?

5. By what proposed mechanisms does nicotinamide work?

6. Were the gender differences observed in this study believable?

7. What may be the clinical implications of this article?

ANSWERS

1. Sun protection has usually been thought of in terms of protection from UV-induced erythema. Sunscreens, until recently, were graded according to “sun protection factor” (SPF), which is a multiple of the sunlight exposure time required for erythema to develop. However, it is also known that UV induces immune suppression, which may play a role in skin cancer development. It is therefore rational to seek protection from UV-induced immune suppression as well. In this study, Damian et al. (2008) demonstrated that topical 5% nicotinamide applied both before and after solar-simulated UV (ssUV) exposure prevented ssUV-induced immunosuppression as measured by decreased erythema and induration of the Mantoux reaction—a delayed hypersensitivity (type IV) reaction that in this study served as a model for immune competence—when compared with a non-irradiated control. All participants in the study were given bacillus Calmette-Guérin (BCG) vaccine, which led to all being Mantoux positive prior to the study. The authors had also previously shown that UV exposure attenuates Mantoux reactions in BCG-vaccinated volunteers (Damian et al., 2008; Friedmann et al., 2004).

The minimal erythema dose (MED) was unchanged by nicotinamide applied before or after ssUV exposure. These results are consistent with previous studies that reported that nicotinamide could prevent UV-induced immunosuppression and carcinogenesis in mice (Gensler, 1997; Hersey et al., 1983).

The male subjects in the study, in the absence of nicotinamide, demonstrated greater ssUV-induced immunosuppression of the Mantoux response than women; in men the ssUV-induced immunosuppression occurred at all doses of ssUV. Female subjects were significantly immunosuppressed only by the highest dose of ssUV. Interestingly, when the components of ssUV were given separately in the form of UVA alone or UVB alone, the Mantoux responses were unchanged; thus, immunosuppression of the Mantoux responses did not occur with UVA or UVB alone.

In an attempt to understand the mechanisms at play, Damian et al. demonstrated through microarray analysis that ssUV downregulates apoptotic pathways, energy metabolism pathways, and immune function/complement pathways, whereas the application of nicotinamide before and after ssUV essentially prevented their downregulation.

2. The relationship between sunlight and the development of skin cancer has previously been established. On a cellular level, different wavelengths of UV radiation induce different types of DNA damage. UVB and UVC are capable of exciting the DNA molecule directly, leading to mutagenesis through the production of cyclobutane–pyrimidine dimers and 6,4-photoproducts. UVA is not energetic enough to excite DNA molecules directly; rather, it exerts its effect through the generation of reactive oxygen species, which precipitate a series of reactions leading to mutagenesis.

In addition to the direct effects of UV on cells, studies have shown that UVB initiates a selective immunosuppression that has been described in humans (Hersey et al., 1983; Kelly et al., 2000) as well as in experimental animals (Fisher and Kripke, 1977; De Fabo and Kripke, 1979; De Fabo and Kripke, 1980). It is thought that this UV-induced immunosuppression is a critical step in UV carcinogenesis, as T-cell responses are known to protect against neoplasia. This UV-induced immunosuppression prevents the immunologic destruction of highly antigenic UV-induced skin cancers (Fisher and Kripke, 1977; De Fabo and Kripke, 1979; De Fabo and Kripke, 1980). From an epidemiologic standpoint, support for a role of immunosuppression in human skin cancer also comes from observations in transplant patients who receive immunosuppressive treatment; these patients have enhanced susceptibility to sunlight-induced skin tumors and commonly develop tumors.

Furthermore, there is a quantitative relationship between the amount of UV exposure and number of skin cancers. For example, mice with increased susceptibility to UV-induced immunosuppression produced greater numbers of skin cancers when exposed to higher amounts of UV (Noonan et al., 2003).

3. In this study UV radiation was given in the form of ssUV, which closely approximates natural sunlight. Doses equivalent to those encountered on a daily basis—ssUV equivalent to 8 minutes of sun exposure—were given on 3 consecutive days employing a protocol used by the European Cosmetic, Toiletry and Perfumery Association (COLIPA): the COLIPA SPF test method, ref. 94/289,21 (1994). At this dose, more than 40% immunosuppression of the Mantoux response was observed. Immune suppression appears to occur prior to erythema development, as UV doses well below the average MED induced 25% immunosuppression.

It is interesting to note that in this study doses of UVA and UVB given separately did not induce immunosuppression. In many other studies in both animals and humans, UVB has been shown to be immunosuppressive (Hersey et al., 1983; Kelly et al., 2000). This may be related to the dosage used in this study and possibly indicates that the doses of UVB used were insufficient to induce immune suppression.

4. Based on the current definition of “sunscreen,” nicotinamide is not a new sunscreen. Sunscreens are used to prevent or slow the time to UV-induced erythema; nicotinamide did not change the MED of UVB and thus did not prevent “sunburn.”

5. Nicotinamide, the active form of vitamin B3, is known to be an endogenous inhibitor of the nuclear enzyme poly-ADP-ribose polymerase (PARP), which in response to DNA damage regulates the expression of immunomodulatory proteins such as inducible nitric oxide synthetase, intercellular adhesion molecule 1, major histocompatibility complex II, and NF-KB (Virag and Szabo, 2002).

The mechanisms by which nicotinamide inhibits UV-induced immunosuppression have not been fully elucidated, but several hypotheses have been suggested. Damian et al. suggest that nicotinamide prevents ssUV-induced downregulation of the telomerase pathway. Telomerase ordinarily inhibits UV-induced DNA damage by lengthening telomeres. It has been shown that UV irradiation inhibits telomerase and increases the rate of telomere shortening (Kosmadeki and Gilchrest, 2004), and that nicotinamide blocks this inhibition. ssUV also induces cellular energy depletion, an effect that is blocked by nicotinamide, as nicotinamide is metabolized into NAD+, an essential coenzyme in ATP production and the sole substrate of PARP. Although modest PARP activation may cause DNA repair, overactivation can cause cell death, and thus nicotinamide-induced inhibition of PARP may lead to reduced cellular damage.

6. Physicians who treat skin cancer may find the gender difference found in this study to be at odds with clinical experience. They may rationalize that skin cancer is not a gender-specific disease. However, Damian and colleagues cite two references to support their claim that men have “both a higher incidence and mortality from skin cancer” (Damian et al., 2008). The first is a study of 916 patients in Arizona who were followed over many years; the study notes that males had a higher incidence of basal cell carcinoma and squamous cell carcinoma than females (Foote et al., 2001). The second article. by Molife et al. (2001), mentions but does not expand on an observation that women with melanoma have a higher survival rate than do men. The article discusses gender and survival rates in eight types of cancer other than melanoma.

In the current report, Damian et al. found that men showed UV-induced immunosuppression at all levels of ssUV, whereas women showed immunosuppression at only the very highest levels of ssUV. The authors adjusted for risk factors such as smoking, but, because of the small number of women in the study, they were unable to account for the effect of sex hormones (of the women, four were on oral contraceptives, five were postmenopausal, and nine were premenopausal). In studies of UV-induced immunosuppression in mice, male mice were more likely to be immunosuppressed than female mice (Hiramoto et al., 2004). However, this finding was reversed by injecting males with 17--estradiol before irradiation and applying a topical estrogen-receptor antagonist to female mice before irradiation.

7. Topical 5% nicotinamide applied either before or after sun exposure inhibits UV-induced immunosuppression. Because UV-induced immunosuppression has been linked to carcinogenesis, one possible conclusion is that topical 5% nicotinamide may prevent UV-induced carcinogenesis. On the other hand, this conclusion will need to be investigated further in long-term prospective studies. It is an intriguing and exciting prospect, as skin cancer is the most common malignancy in humans. If topical 5% nicotinamide is proven to be a preventive agent, it would be one more tool in the armamentarium of skin cancer prevention.

Furthermore, if the gender difference in ssUV-induced immunosuppression found in this study is valid, then topical nicotinamide use may be important to recommend for male patients. The sample size of women in this study was limited, and additional studies investigating the responses of pre- and postmenopausal women to UV radiation may shed more light on the role of estrogen and UV-induced immunosuppression in humans.

This study has broadened our concepts of sun protection. Not only should sunscreens be used to prevent erythema and burning, but perhaps topically applied molecules are able to prevent UV-induced immunosuppression and thus to inhibit UV-induced carcinogenesis.

REFERENCES

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Damian DL, Patterson CRS, Stapelberg M, Park J, Barnetson RS, Halliday GM (2008) UV radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide. J Invest Dermatol 128:447–54

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Fisher M, Kripke M (1977) Systemic alteration induced in mice by ultraviolet irradiation and its relationship to ultraviolet carcinogenesis. Proc Natl Acad Sci USA 74:1688–92

Foote JA, Harris RB, Giuliano AR, Roe DJ, Moon TE, Cartmel B et al. (2001) Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults. Int J Cancer 95:7–11

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Kosmadeki MG, Gilchrest BA (2004) The role of telomeres in skin aging/photoaging. Micron 35:155–9

Molife R, Lorigan P, MacNeil S (2001) Gender and survival in malignant melanoma. Cancer Treat Rev 27:201–9

Noonan FP, Muller HK, Fears TR, Kusewitt DF, Johnson TM, De Fabo EC (2003) Mice with genetically determined high susceptibility to ultraviolet (UV)-induced immunosuppression show enhanced UV carcinogenesis. J Invest Dermatol 121:1176–81

Ulrich C, Stockfleth E (2007) Azathioprine, UV light, and skin cancer in organ transplant patients—do we have an answer? Nephrol Dial Transplant 22:1027–9

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^1^Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA