RESUMEN
Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA's mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects.
Asunto(s)
Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/efectos de la radiación , Terapia PUVA , Factor de Activación Plaquetaria/inmunología , Animales , Candida albicans/inmunología , Candidiasis/tratamiento farmacológico , Candidiasis/inmunología , Candidiasis/patología , Terapia Combinada/métodos , Femenino , Ficusina/farmacología , Humanos , Hipersensibilidad Tardía/tratamiento farmacológico , Hipersensibilidad Tardía/inmunología , Hipersensibilidad Tardía/patología , Tolerancia Inmunológica/inmunología , Terapia de Inmunosupresión/métodos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interleucina-10/inmunología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Masculino , Ratones , Ratones Noqueados , Terapia PUVA/efectos adversos , Terapia PUVA/métodos , Glicoproteínas de Membrana Plaquetaria/deficiencia , Glicoproteínas de Membrana Plaquetaria/inmunología , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Psoriasis/patología , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Transducción de Señal/efectos de la radiaciónRESUMEN
A combination of psoralens and ultraviolet A radiation is widely used to treat psoriasis. Long-term, high-dose exposure to psoralen + ultraviolet A is associated with an increased risk of nonmelanoma skin cancer, particularly squamous cell carcinoma. In this study, we used p53 mutations as a molecular marker to determine the separate contributions of psoralen + ultraviolet A and other ultraviolet exposures, such as ultraviolet B for skin cancer development in psoralen + ultraviolet A-treated psoriasis patients. The results indicated that of 69 tumors analyzed, 37 (54%) tumors had one or more p53 mutations. Of 37 tumors with mutations, 17 (46%) tumors had only ultraviolet-type mutations, two (5%) tumors had only psoralen + ultraviolet A-type mutations, and 18 (49%) tumors had both types of mutations. Interestingly, psoralen + ultraviolet A-type p53 mutations were more frequent than ultraviolet type in tumors arising in patients with high-dose exposure to psoralen + ultraviolet A. Field cancerization and tumor heterogeneity appeared to occur frequently in the same patient and even in the same tumor. This study's data suggest that psoralen + ultraviolet A-induced p53 mutations may play an important part in the development of nonmelanoma skin cancer in psoralen + ultraviolet A-treated patients, but these mutations are likely to act in concert with the effects of other carcinogenic exposures, particularly ultraviolet B, in the development of skin cancer.