RESUMEN
Histamine H1 receptor (H1R) gene is upregulated in patients with pollinosis; its expression level is highly correlated with the nasal symptom severity. Antihistamines are widely used as allergy treatments because they inhibit histamine signaling by blocking H1R or suppressing H1R signaling as inverse agonists. However, long-term treatment with antihistamines does not completely resolve toluene-2,4-diisocyanate (TDI)-induced nasal symptoms, although it can decrease H1R gene expression to the basal level, suggesting additional signaling is responsible for the pathogenesis of the allergic symptoms. Here, we show that treatment with suplatast tosilate in combination with antihistamines markedly alleviates nasal symptoms in TDI-sensitized rats. Suplatast suppressed TDI-induced upregulation of IL-9 gene expression. Suplatast also suppressed ionomycin/phorbol-12-myristate-13-acetate-induced upregulation of IL-2 gene expression in Jurkat cells, in which calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling is known to be involved. Immunoblot analysis demonstrated that suplatast inhibited binding of NFAT to DNA. Furthermore, suplatast suppressed ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells, in which CN/NFAT signaling is also involved. These data suggest that suplatast suppressed NFAT-mediated IL-9 gene expression in TDI-sensitized rats and this might be the underlying mechanism of the therapeutic effects of combined therapy of suplatast with antihistamine.
Asunto(s)
Antialérgicos/farmacología , Arilsulfonatos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Hipersensibilidad/tratamiento farmacológico , Interleucina-9/genética , Factores de Transcripción NFATC/genética , Enfermedades Nasales/tratamiento farmacológico , Compuestos de Sulfonio/farmacología , 2,4-Diisocianato de Tolueno/toxicidad , Animales , Antialérgicos/uso terapéutico , Arilsulfonatos/uso terapéutico , Calcineurina/fisiología , Células Cultivadas , Quimioterapia Combinada , Expresión Génica/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/uso terapéutico , Hipersensibilidad/genética , Interleucina-9/metabolismo , Masculino , Factores de Transcripción NFATC/fisiología , Enfermedades Nasales/genética , Ratas , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Transducción de Señal/efectos de los fármacos , Compuestos de Sulfonio/uso terapéuticoRESUMEN
Histamine H(1) receptor (H1R) gene is up-regulated in patients with allergic rhinitis, and its expression level strongly correlates with the severity of symptoms. However, the mechanism underlying this remains unknown. Here we report the mechanism of H1R gene up-regulation. The luciferase assay revealed the existence of two promoter regions, A and B1. Two AP-1 and one Ets-1 bound to region A, while Ku86, Ku70, and PARP-1 bound to region B1. Ku86 was responsible for DNA binding and poly(ADP-ribosyl)ated in response to phorbol-12-myristate-13-acetate stimulation, inducing its dissociation from region B1 that is crucial for promoter activity. Knockdown of Ku86 gene enhanced up-regulation of H1R gene expression. Experiments using inhibitors for MEK and PARP-1 indicate that regions A and B1 are downstream regulatory elements of the PKCδ/ERK/PARP-1 signaling pathway. Data suggest a novel mechanism for the up-regulation of H1R gene expression.
Asunto(s)
Antígenos Nucleares/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Regiones Promotoras Genéticas , Receptores Histamínicos H1/genética , Acetato de Tetradecanoilforbol/farmacología , Transcripción Genética , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Orden Génico , Humanos , Autoantígeno Ku , Masculino , Poli(ADP-Ribosa) Polimerasas/metabolismo , Unión Proteica/efectos de los fármacos , Proteína Quinasa C-delta/metabolismo , Ratas , Receptores Histamínicos H1/metabolismo , Elementos de Respuesta , Transducción de Señal , Factores de Transcripción/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
A phase-shifting laser diode interferometer that uses direct pulse modulation is proposed and demonstrated. We found that a laser beam with a wide range of wavelength variation at constant optical power could be generated when a pulsed current was injected into the laser diode. We constructed a highly accurate interferometer by using a pair of interferometers. Several experiments, such as observations of temporal interference signals and spatial interferograms, measurement of a concave mirror, and duplicate measurements, confirmed the characteristics of pulse modulation and demonstrated the effectiveness of our technique.