Ultraviolet-B (UVB, 280-320 nm) radiation can promote the induction of skin cancer by two mechanisms: damage of epidermal DNA and suppression of the immune system, allowing the developing tumor to escape immune surveillance. The mixed lymphocyte reaction (MLR) and the mixed epidermal cell lymphocyte reaction (MECLR) are commonly used methods to study the immunosuppressive effects of UVB radiation. To obtain a better understanding of the mechanism by which UVB radiation decreases the alloactivating capacity of in vitro-irradiated cells, action spectra for the MLR and MECLR were determined. Suspensions of peripheral blood mononuclear cells or epidermal cells were irradiated with monochromatic light of 254, 297, 302 or 312 nm and used as stimulator cells in the MLR or MECLR. Using dose-response curves for each wavelength, the action spectra were calculated. Both MLR and MECLR action spectra had a maximum at 254 nm and a relative sensitivity at 312 nm that was a thousand times lower than at 254 nm. Strikingly, the action spectra corresponded very closely to the action spectra that were found by Matsunaga et al. (Photochem. Photobiol. 54, 403-410, 1991) for the induction of thymine dimers and (6-4)photoproducts in irradiated calf thymus DNA solutions, strongly suggesting that the UV-induced abrogation of the MLR and MECLR responses is mediated by UV-induced DNA damage. Furthermore, the action spectra for the MLR and MECLR were similar, suggesting that they share a common mechanism for UV-induced suppression.
Cis-urocanic acid (UCA), formed in the stratum corneum by UV irradiation of trans-UCA has been proposed as a mediator of UV-induced immunosuppression in the skin. In this study, we examined the in vitro effect of cis-UCA (6-100 micrograms/mL) on the human mixed lymphocyte reaction (MLR) and the mixed epidermal cell lymphocyte reaction (MECLR). Addition of cis-UCA (purified or in a mixture with trans-UCA) did not affect the MLR but was able to induce a 20% suppression of the MECLR responses. Because this effect of cis-UCA on the MECLR was not as strong as could be expected from previous in vivo results, we designed a set of experiments in order to enhance the in vitro immunosuppressive capacity of cis-UCA. Firstly, we preincubated epidermal cells with UCA (50 micrograms/mL). for 3 or 6 days before culture in the MECLR because in vivo repeated UV exposure can lead to a photostationary state, where cis-UCA may be present for several weeks. This pretreatment with cis-UCA resulted in a maximal decrease of the MECLR response of 27%, whereas trans-UCA had no effect. Secondly, we investigated whether UVB irradiation of epidermal cells could make cells more sensitive to cis-UCA. However, addition of trans- or cis-UCA did not potentiate the reduced alloactivating capacity of UVB-irradiated cells. Finally, we examined the possibility of a synergistic effect of cis-UCA with histamine. Addition of histamine suppressed the MLR and MECLR responses, but neither cis- nor trans-UCA were able to modulate this decrease. We conclude that cis-UCA can partly downregulate the human MECLR but not the MLR. The mechanism involved in this differential downregulation is not known. In this respect it is striking that cis-UCA dose not potentiate the UVB- or histamine-induced suppression of the MECLR.
Ultraviolet radiation has been shown to suppress the (skin) immune system both in animal species and in humans. Whether sunscreens can prevent immunosuppression is a matter of debate. This study investigated the protective capacity of a commercial sunscreen lotion in humans. Part of the right arm of healthy volunteers was exposed to erythemagenic ultraviolet B doses of 160 mJ per cm2 for four consecutive days. Before irradiation, sunscreen was applied either directly onto the skin or onto a piece of quartz fixed to the skin (to avoid penetration of the sunscreen in the epidermis where it cannot block the photoisomerization of trans-urocanic acid in cis-urocanic acid in the stratum corneum). The control group was irradiated without prior application of sunscreen. Four h after the last irradiation, epidermal sheets were obtained by the suction-blister method from both arms and epidermal cells were used as stimulator cells in the mixed epidermal cell lymphocyte reaction. Responses directed to epidermal cells derived from irradiated skin were expressed as percentages of responses directed to epidermal cells derived from the nonirradiated left arm. The mixed epidermal cell lymphocyte reaction responses in the control group were found to be significantly increased (205%). This enhancement of the mixed epidermal cell lymphocyte reaction responses was associated with an influx of CD36+DR+ macrophages in the irradiated skin. Application of the sunscreen, either onto a piece of quartz or directly onto the skin, prevented the increase of the mixed epidermal cell lymphocyte reaction responses and the influx of CD36+DR+ cells. In an earlier study, volunteers were exposed three times weekly to suberythemagenic doses of ultraviolet B over 4 wk, resulting in mixed epidermal cell lymphocyte reaction responses that were decreased to 20%. The same sunscreen was not able to prevent this suppression. These contradicting results indicate that the protective effect of sunscreens with respect to ultraviolet-induced immunomodulation is critically dependent on the choice of ultraviolet treatment.
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