Meira Bosnic

Ultraviolet A radiation (320-400 nm) protects hairless mice from immunosuppression induced by ultraviolet B radiation (280-320 nm) or cis-urocanic acid.

T cell-mediated immune function, here measured as the contact hypersensitivity reaction, is readily suppressed by moderate exposure of mice to ultraviolet B (UVB) or solar-simulated radiation (SSUV), or by topical application of cis-urocanic acid. The effect of ultraviolet A (UVA) radiation on immune function has been unclear. Here we have demonstrated that when UVA radiation from a fluorescent tube source was rigorously filtered to remove contaminating UVB radiation, it was immunologically innocuous at physiologically relevant doses. Furthermore, we have found that mice exposed to UVA radiation, either immediately after, or up to 24 h before, immunosuppressive treatment with either UVB radiation, SSUV or cis-urocanic acid, became refractory to the immunosuppression and retained more normal contact hypersensitivity. A greater UVA exposure reversed the immunosuppression more effectively. The results suggest that there are immunologically significant interactions between UV wavebands, and that UVA exposure may induce a relatively long-lived immunoprotective photoproduct, as yet unidentified, that can inhibit the activity of epidermal cis-urocanic acid and thus provide protection from photoimmunosuppression.

A garlic extract protects from ultraviolet B (280-320 nm) radiation-induced suppression of contact hypersensitivity

Abstract Lyophilized aged garlic extract has been incorporated at concentrations of 0.1%, 1% and 4% by weight into semipurified powdered diets and fed to hairless mice. Under moderate UVB exposure conditions resulting in 58% suppression of the systemic contact hypersensitivity response in control‐fed mice, a dose‐responsive protection was observed in the garlic‐fed mice; contact hypersensitivity in the UVB‐exposed mice fed 4% garlic extract was suppressed by only 19%. If the UVB exposure was replaced by topical application of one of a series of lotions containing increasing concentrations of cis‐urocanic acid, a dose‐responsive suppression of contact hypersensitivity was demonstrated in control‐fed mice (urocanic acid at 25, 50, 100 and 200 μg per mouse resulting in 22–46% suppression). Mice fed a diet containing 1% aged garlic extract were partially protected from cis‐urocanic acid‐induced suppression of contact hypersensitivity, with greater protection from the lower concentrations of urocanic acid. Mice fed a diet containing 4% aged garlic extract were protected from all concentrations of urocanic acid. The results indicate that aged garlic extract contains ingredient(s) that protect from UVB‐induced suppression of contact hypersensitivity and suggest that the mechanism of protection is by antagonism of the cis‐urocanic acid mediation of this form of immunosuppression.

Dependence of photocarcinogenesis and photoimmunosuppression in the hairless mouse on dietary polyunsaturated fat

A series of semi-purified diets containing 20% fat by weight, of increasing proportions (0, 5%, 10%, 15% or 20%) of polyunsaturated sunflower oil mixed with hydrogenated saturated cottonseed oil, was fed to groups of Skh:HR-1 hairless mice during induction and promotion of photocarcinogenesis. The photocarcinogenic response was of increasing severity as the polyunsaturated content of the mixed dietary fat was increased, whether measured as tumour incidence, tumour multiplicity, progression of benign tumours to squamous cell carcinoma, or reduced survival. At the termination of the study approximately 6 months following the completion of the 10-week chronic UV irradiation treatment, when most mice bore tumours, the contact hypersensitivity (CHS) reactions in those groups supporting the highest tumour leads (fed 15% or 20% polyunsaturated fat), were significantly suppressed in comparison with the mice bearing smaller tumour loads (fed 0, 5% or 10% polyunsaturated fat). When mice were exposed acutely to UV radiation (UVR), a diet of 20% saturated fat provided almost complete protection from the suppression of CHS, whereas feeding 20% polyunsaturated fat resulted in 57% suppression; the CHS of unirradiated mice was unaffected by the nature of the dietary fat. These results suggest that the enhancement of photocarcinogenesis by the dietary polyunsaturated fat component is mediated by an induced predisposition to persistent immunosuppression caused by the chronic UV irradiation, and supports the evidence for an immunological role in dietary fat modulation of photocarcinogenesis in mice.

Lack of metallothionein-I and -II exacerbates the immunosuppressive effect of ultraviolet B radiation and cis-urocanic acid in mice

The effect of a null mutation for the metallothionein (MT)‐I and ‐II isoforms in mice on the immunosuppressive action of ultraviolet B (UVB; 280–320 nm) radiation has been examined. Mice were exposed to a series of increasing daily UVB doses, each dose administered to the dorsum on 3 consecutive days. Erythema was assessed, and measured as its oedema component by the post‐irradiation dorsal skinfold thickness, but there was no effect of the null mutation (MT–/–) observed after 3 × 3·4 kJ/m2 of UVB radiation. Immune function was assessed by the contact hypersensitivity (CHS) response, which was initiated by sensitization on unirradiated abdominal skin, and thus demonstrated the systemic effects of dorsal treatments. In comparison with the wild‐type MT+/+ mouse, the MT–/– mouse was significantly more immunosuppressed by moderate daily UVB doses (1·75–5·9 kJ/m2). When topically applied cis‐urocanic acid (cis‐UCA) replaced UVB radiation as the immunosuppressive agent, contact hypersensitivity in MT–/– mice was again markedly more suppressed than in MT+/+ mice, in a dose‐responsive manner. The results infer that MT, which was shown immunohistochemically to be strongly induced in the epidermis of MT+/+ mice, but to be absent in MT–/– epidermis, has the potential to protect from photoimmunosuppression, and that the mechanism of action may be via the inactivation of the epidermal UVB‐photoproduct, cis‐UCA.

LACK OF CORRELATION BETWEEN SUPPRESSION OF CONTACT HYPERSENSITIVITY BY UV RADIATION AND PHOTOISOMERIZATION OF EPIDERMAL UROCANIC ACID IN THE HAIRLESS MOUSE

Abstract The immunological consequences of exposure to UVA (320–400 nm) radiation are unclear. This study describes the relationship between the generation of epidermal cis‐urocanic acid and the ability to respond to a contact‐sensitizing agent, in hairless mice exposed to different UV radiation sources, which incorporate successively greater short‐wavelength cutoff by filtration of the radiation from fluorescent UV tubes. Mice were exposed to these radiation sources at doses systematically varying in UVB radiation content but supplying increasing proportions of UVA radiation. All radiation sources were found to generate approximately 35%cis‐urocanic acid in the epidermis, thus normalizing the sources for cis‐urocanic acid production. However, only those sources richest in short‐wavelength UVB resulted in suppression of the systemic contact hypersensitivity response. These sources also induced the greatest erythema reaction, measured as its edema component, in the exposed skin. A strong correlation was thus demonstrated between the induction of edema and the suppression of contact hypersensitivity, but there appeared to be no correlation between the generation of epidermal cis‐urocanic acid and suppression of contact hypersensitivity. The sources richest in UVA content did not result in suppression of contact hypersensitivity: furthermore mice previously irradiated with such UVA‐rich sources were refractory to the immunosuppressive action of exogenous cis‐urocanic acid. A protective effect of the increased UVA content thus appeared to be inhibiting immunosuppression by the available endogenously generated or exogenously applied cis‐urocanic acid.

Suppressive Effect of 2-Acetyl-4-Tetrahydroxybutylimidazole on Contact Hypersensitivity in the Skh: HR Hairless Mouse

The compound 2-acetyl-4-tetrahydroxybutylimidazole (THI), a component of ammonia caramel, has been shown to cause lymphopenia and to impair several immune functions in rats and mice. In this study we show that THI effectively suppresses contact hypersensitivity dose responsively in the hairless mouse, whether administered topically or orally. The suppression was shown to be prevented by topical administration of the histamine antagonist, cimetidine, and by the dipeptide, carnosine. Splenocytes from THI-treated mice failed to elicit normal contact hypersensitivity when transferred to naive mice. This suggests that THI acts by modifying splenocyte function, perhaps via a histamine-like receptor site(s).

Dietary zinc, photoimmunosuppression and metallothionein (MT)

Zn is an essential trace element, a deficiency resulting in skin abnormalities in particular [1]. Human skin contains approximately 20% of the body’s Zn stores. It is notable that epidermal Zn is found unevenly distributed, being histochemically demonstrated to be concentrated in the stratum germinativum, an observation that has led to the suggestion that Zn may have an association with the terminal differentiation of epidermal cells, which produces the stratified epidermal structure, and thus may be involved in the regulation of epidermal proliferation [2, 3]. Zn deficiency causes characteristic hyperkeratotic changes, abnormal keratohyalin formation, and depresses dermal collagen synthesis; the skin thus seems to be particularly sensitive to the Zn status of the animal.

Interaction of UVB-absorbing Sunscreen Ingredients with Cutaneous Molecules May Alter Photoimmune Protection¶

Studies of the photoimmunoprotective properties of sunscreens have produced disparate results. In this study in hairless mice, we compared two UVB absorbers, 2‐ethylhexyl‐p‐methoxycinnamate (2‐EHMC) and octyl‐N‐dimethyl‐p‐aminobenzoate (o‐PABA), individually formulated in a common base lotion with a sunburn protection factor of 6. We measured their capacity to protect against suppression of the contact hypersensitivity (CHS) induced by three daily exposures of the dorsum to 6× the minimal erythemal/edematous dose (MED) of solar‐simulated UV radiation (SSUV), in comparison with base lotion–treated mice exposed to 3 × 1 MED of SSUV. All treatments produced a similar minimal erythema. CHS was equally suppressed in mice irradiated through o‐PABA and base lotion, but the suppression was significantly reduced in mice irradiated through 2‐EHMC. Neither UVB absorber inhibited the epidermal photoisomerization to the immunosuppressive mediator, cis‐urocanic acid. However, when mice were treated with exogenous cis‐urocanic acid topically on the dorsum, but not when injected subcutaneously on the abdomen, suppression of CHS was observed in o‐PABA– and base lotion–treated mice, but not in 2‐EHMC–treated mice. Thus, the enhanced immunoprotection in mice irradiated through 2‐EHMC apparently resulted from the direct inactivation of epidermal cis‐urocanic acid by 2‐EHMC. We conclude that comparative assessment of photoimmunoprotection by UV absorbers requires SSUV, erythemally matched exposures and consideration of potential interactions with cutaneous molecules.

Epidermal Urocanic Acid and Suppression of Contact Hypersensitivity by Ultraviolet Radiation in Monodelphis domestica

A single specific epidermal photoreceptor for the immunosuppressive action of UV radiation has not been defined, although separate evidence is accruing in favour of each of two candidates, trans-urocanic acid and DNA. In Monodelphis domestica, specific photoreactivation repair of UV radiation-induced pyrimidine dimers has been shown to abrogate the suppression of contact hypersensitivity (CHS), thus suggesting that DNA is the target for this impairment. However, the both haired and hairless mice, immunosuppressive effects of UV radiation have been reproduced by the exogenous administration of the UV photoproduct of urocanic acid, cis-urocanic acid. We show here that the epidermis of M. domestica contains urocanic acid, that UV irradiation of the shaved dorsal skin has resulted in an increase in epidermal cis-urocanic acid and that the topical application of a cis-urocanic acid-containing lotion significantly depressed the capacity of Monodelphis to respond to contact sensitisers, in a manner analogous to these responses in the hairless mouse. Therefore in Monodelphis, suppression of CHS by UV irradiation appears to involve both urocanic acid photo-isomerisation and epidermal DNA damage.