RESUMEN
Urocanic acid (UCA) has been shown to mediate the UVB radiation-induced immunosuppression initiated in the skin by UV-induced isomerization from the trans to the cis isomer. However, the mechanism by which cis-UCA acts is still unclear. Therefore, the present study was undertaken to determine the effect of trans- and cis-UCA on cyclic adenosine 3',5'-monophosphate (cAMP) synthesis in human dermal fibroblasts, Golden Syrian hamster hepatocytes and in the human adenocarcinoma cell line, HT29. Neither trans- nor cis-UCA was able to stimulate cAMP synthesis directly in any of the models tested. In human dermal fibroblasts, cis-UCA, in contrast to trans-UCA, specifically inhibited cAMP synthesis induced by either prostaglandin (PG) E1 or PGE2 with a maximum inhibitory effect of 25-30% at cis-UCA concentrations greater than 1 microM and half-maximum inhibitory effect (EC50) observed at 35 nM. The effect of cis-UCA was not to stimulate phosphodiesterase and cAMP breakdown. The inhibitory effect of cis-UCA (an imidazole derivative) was not mediated through stimulation of the alpha 2-adrenergic receptor. The inhibitory effect of cis-UCA on stimulated cAMP synthesis was a function of the cell density and was only significant when the fibroblasts were confluent or postconfluent. In contrast to the studies with human dermal fibroblasts, an inhibitory effect of cis-UCA was not observed in either isolated hamster hepatocytes or HT29 cells, in which cAMP synthesis was stimulated by glucagon and vasoactive intestinal peptide, respectively. These results point to a possible regulation of cAMP synthesis in fibroblasts as one mechanism by which cis-UCA exerts its biological effect in the skin.
Asunto(s)
AMP Cíclico/biosíntesis , Ácido Urocánico/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Alprostadil/farmacología , Animales , Tartrato de Brimonidina , Células Cultivadas , Colon/efectos de los fármacos , Cricetinae , Dinoprostona/farmacología , Epinefrina/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Células HT29 , Histamina/farmacología , Humanos , Hígado/efectos de los fármacos , Mesocricetus , Quinoxalinas/farmacología , Ácido Urocánico/administración & dosificaciónRESUMEN
Photocarcinogenesis represents the sum of a complex of simultaneous and sequential biochemical events that ultimately lead to the occurrence of skin cancer. These events, initiated by UV radiation of appropriate wavelength, include the formation of DNA photoproducts: DNA repair; mutation of proto-oncogenes and tumor suppressor genes; UV-production of radical species with subsequent effects on mutation and extra-nuclear function; and other epigenetic events that influence the course of carcinogenesis. The epigenetic influences may include immunological responses, antioxidant defenses, and dietary factors. This review represents an effort to provide current research results in the aforementioned areas and an attempt to meld these events into a comprehensive overview of photocarcinogenesis. If effective prevention and intervention strategies for skin cancer are to developed, a more thorough understanding of the disease process is imperative.
Asunto(s)
ADN/efectos de la radiación , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Cutáneas/epidemiología , Rayos Ultravioleta , Animales , Aductos de ADN , Daño del ADN , Reparación del ADN , Genes Supresores de Tumor , Humanos , Mutación , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/genética , Proto-Oncogenes , Roedores , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genéticaRESUMEN
It has been postulated that ultraviolet radiation (UVR) alters antigen presentation by macrophages. This is thought to be due, in part, to inhibition of macrophage-derived interleukin 1 (IL-1), which is a hormone-like factor with immunoregulatory functions. Conventional stimulator cells for antigen presentation are macrophages; however, other cell types such as epidermal Langerhans cells are capable of antigen presentation. Keratinocytes also play a role in the immune system by providing a factor with IL-1-like activity, termed Epidermal cell-derived Thymocyte-Activating Factor (ETAF). The purpose of this study was to determine whether UVR affects alloantigen presentation by epidermal cells and if so, whether the UV-induced change is due to UVR alteration in ETAF activity. Epidermal cells from UV-treated BALB/c mice (UV-EC) or from non-UV-treated mice (EC) were x-irradiated and then cocultured for 5 days with allogeneic T cells from C57Bl/6 mice. UV-EC caused less T-cell stimulation than did EC from non-UV-treated animals. When chromatography purified fractions of ETAF were added to cultured UV-EC, partial restoration of T-cell stimulation was seen. These results suggest that this UV-induced defect in alloantigen presentation is due, in part, to decreased ETAF activity.