CALCITONIN-GENE-RELATED PEPTIDE AND NITRIC-OXIDE ARE INVOLVED IN ULTRAVIOLET RADIATION-INDUCED IMMUNOSUPPRESSION

Contact hypersensitivity responsiveness to dinitrofluorobenzene is dep ressed in mice that are sensitized through skin sites exposed to ultra violet (UV) radiation. Local impairment of contact hypersensitivity by UV has been associated with a reduction in antigen-presenting cell ac tivity within UV-irradiated skin sites marked by a decrease in the den sity of Ia-positive epidermal Langerhans cells. Our recent studies hav e demonstrated that neurogenic mediators (e.g. calcitonin gene-related peptide (CGRP) and nitric oxide (NO) contribute to cutaneous inflamma tion following exposure of rats to high-dose UV radiation. Since CGRP and NO inhibit antigen presentation by dendritic cells in vitro, we ha ve investigated the possible involvement of CGRP and NO in local immun osuppression in UV-irradiated rodents. Hindpaw skin of Sprague-Dawley rats and back skin of UV-susceptible C57BL/6 mice was exposed to acute UV radiation (2.0 J/cm(2) and 0.5 J/cm(2), respectively). Alterations in cutaneous CGRP content were analyzed by a specific radioimmunoassa y (RIA). In separate experiments, the CGRP receptor antagonist CGRP-(8 -37) (10(-5) M) and the nitric oxide synthase inhibitor N-G-nitro-L-ar ginine methyl ester (L-NAME) (2 X 10(-5) M) were topically applied to UV-exposed skin before induction of contact hypersensitivity with dini trofluorobenzene. Finally, we examined the effects of UV irradiation a nd epicutaneous application of CGRP on Ia-positive Langerhans cells by immunohistochemical analysis of epidermal sheets. It was found that U V exposure lead to a decrease in skin CGRP levels starting already 2 h after irradiation and reaching a minimum (less than 40% of non-irradi ated control skin) at 6-12 h. Contact hypersensitivity reactions were significantly suppressed by UV radiation in rat skin (by 51%) and muri ne skin (by 80%). Topical administration of both CGRP-(8-37) and L-NAM E before sensitization restored the capacity to respond to haptens app lied to UV-exposed skin. Both UV exposure and topical CGRP reduced the density of Ia-positive epidermal cells. Our data indicate that CGRP m ay be released from sensory neurons following cutaneous UV irradiation and that CGRP and NO contribute to UV-induced local immuno-suppressio n. Moreover, topical administration of CGRP or its antagonist may be a ble to modulate epidermal Langerhans cell activity in vivo.