RESUMEN
One of the mitogen-activated protein kinases, p38, has been found to play a crucial role in various inflammatory responses. In this study, we analyzed the roles of p38α in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis (EAE). p38α(+/-) mice (p38α(-/-) showed embryonic lethality) showed less severe neurological signs than WT mice. Adoptive transfer of lymph node cells (LNC) from sensitized WT mice with MOG(35-55) to naive WT-induced EAE was much more severe compared with the case using LNC from sensitized p38α(+/-) mice. Comprehensive analysis of cytokines from MOG(35-55)-challenged LNC by Western blot array revealed that production of IL-17 was significantly reduced by a single copy disruption of the p38α gene or a p38 inhibitor. Likewise, by a luciferase reporter assay, an electrophoresis mobility shift assay, and characterization of the relationship between p38 activity and IL-17 mRNA expression, we confirmed that p38 positively regulates transcription of the Il17 gene. Furthermore, oral administration of a highly specific p38α inhibitor (UR-5269) to WT mice at the onset of EAE markedly suppressed the progression of EAE compared with a vehicle group. These results suggest that p38α participates in the pathogenesis of EAE through IL-17 induction.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Animales , Ensayo de Cambio de Movilidad Electroforética , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Inhibidores Enzimáticos/uso terapéutico , Femenino , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Ratones , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 14 Activada por Mitógenos/genética , Regiones Promotoras Genéticas , Estabilidad del ARN/genéticaRESUMEN
o-Formyl-substituted beta,beta-difluorostyrenes readily react with NH(2)OH.HCl or NH(4)OAc to afford 3-fluoroisoquinoline derivatives in good yield via (i) the formation of the corresponding oximes or imines and (ii) subsequent intramolecular replacement of a vinylic fluorine by the sp(2) nitrogen of the iminomethyl group (HON=CH- or HN=CH-). Beta,beta-Difluorostyrenes bearing an o-diazenyl group (HN=N-), generated by reduction of the corresponding diazonium ions, undergo a similar substitution to afford 3-fluorinated cinnolines.
Asunto(s)
Compuestos Heterocíclicos con 2 Anillos/síntesis química , Hidrocarburos Fluorados/síntesis química , Iminas/química , Isoquinolinas/síntesis química , Estirenos/química , Compuestos Azo/química , Ciclización , Compuestos Heterocíclicos con 2 Anillos/química , Hidrocarburos Fluorados/química , Isoquinolinas/química , Estructura MolecularRESUMEN
o-Cyano-beta,beta-difluorostyrenes react with organolithiums selectively at the cyano carbon to generate the corresponding sp(2) nitrogen anions, which in turn undergo intramolecular replacement of the vinylic fluorine to afford 3-fluoroisoquinolines. Similarly, the reaction of beta,beta-difluoro-o-isocyanostyrenes with organomagnesiums or -lithiums generates the corresponding sp(2) carbanions on the isocyano carbon. Subsequent cyclization via substitution of the fluorine leads to 3-fluoroquinolines. [reaction: see text]