Gender differences in UV-induced inflammation and immunosuppression in mice reveal male unresponsiveness to UVA radiation

Abstract

Immunosuppression attributed mainly to the UVB (290-320 nm) waveband is a prerequisite for skin cancer development in mice and humans. The contribution of UVA (320-400 nm) is controversial, but in mice UVA irradiation has been found to antagonise immunosuppression by UVB. In other studies of photoimmune regulation, protection mediated via oestrogen receptor-β signalling was identified as a normal endogenous defence in mice, and was shown to depend on UVA irradiation. A gender bias in photoimmune responsiveness was thus suggested, and is tested in this study by comparing the UV-induced inflammatory and immune responses in male and female hairless mice. We report that male mice, which show greater skin thickness than females, developed a less intense but slower resolving sunburn inflammatory oedema, correlated with reduced epidermal expression of pro-inflammatory IL-6 than females following solar simulated UV (SSUV, 290-400 nm) exposure. On the other hand, the contact hypersensitivity reaction (CHS) was more severely suppressed by SSUV in males, correlated with increased epidermal expression of immunosuppressive IL-10. Exposure to the UVB waveband alone, or to cis-urocanic acid, suppressed CHS equally in males and females. However, whereas UVA irradiation induced immunoprotection against either UVB or cis-urocanic acid in females, this protection was significantly reduced or abrogated in males. The results indicate that males are compromised by a relative unresponsiveness to the photoimmune protective effects of UVA, alone or as a component of SSUV. This could explain the known gender bias in skin cancer development in both mice and humans.

Public (Skin) Health perspectives of gender differences in tanning habits and sun protective behaviour: a cross-sectional questionnaire survey

“…Some studies suggest differences between male and female tanning behaviour, such as sun protection use, amount of time spent in the sun, likeliness to use sunbeds and varying risks for sunburn and melanoma [34,35]. According to previously published studies, gender-imbalanced morbidity and mortality rates may root in different cellular and molecular properties of skin cancer [36][37][38]. In our survey, we also found some significant differences in gender-related attitudes and motives regarding having or not having a tanned skin.…”

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

“…That is, males, naturally deficient in estrogen and ER signaling, do not exhibit reductions in contact hypersensitivity induced by solar stimulated radiation, suggesting that females are more protected than males to NMSC. However, the same study demonstrated that male mice exposed to both UVA and UVB had less inflammatory edema compared to females due to their naturally thicker skin (presumably due to increasing thickness of the dermis and subdermal muscle layer) and decreases in levels of proinflammatory IL‐6 specific to males 40. In another study, Sullivan et al 41.…”

CYP11A1 in skin: An alternative route to photoprotection by vitamin D compounds

“…As noted above, in this model, and in human keratinocytes, 1,25D reduces interleukin-6 expression [25,63] and this may be an action of 20OHD as well, though this remains to be tested. There is evidence that metallothionein knockout mice are more susceptible to UV-induced immunosuppression, compared to the wild type [69]. As metallothionein mRNA expression is induced by 1,25D [70], this mechanism might also contribute to the reduction in photoimmune suppression by 1,25D and possibly 20OHD, although whether 20OHD induces metallothionein is unknown at this time..…”