RESUMEN
BACKGROUND: Asthma can frequently be induced or exacerbated by respiratory viral infections. Oxidative stress might also play an essential role in the pathogenesis of allergic airway diseases, indicating that antioxidant therapy may have a potential effect in controlling allergic airway diseases. Recent studies showed that 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) has the potential ability to modulate NADPH oxidase activity, indicating the antioxidant activity of AICAR. This study investigated the inhibitory effects of AICAR as an anti-inflammatory modulator on allergic airway inflammation in murine animal models. METHODS: The anti-inflammatory effects of AICAR were evaluated in two experimental asthma models: (1) an ovalbumin (OVA)-induced experimental asthma model and (2) an OVA plus polyinosinic-polycytidylic acid [poly (I:C)]-induced experimental asthma model to mimic respiratory viral infections. The inhibitory effects of AICAR in poly (I:C)-mediated signalling for NF-kappaB activation and production of TNF-alpha were analysed in vitro. RESULTS: AICAR was shown to have a marginal inhibitory effect in an OVA-induced asthma model. Interestingly, AICAR significantly attenuated poly (I:C)-induced airway hyperresponsiveness and airway inflammation, as shown by the attenuation of the influx of total inflammatory cells and soluble products into bronchoalveolar lavage fluid, such as macrophages, eosinophils, IL-5, IL-13, TNF-alpha and IFN-gamma. AICAR also significantly reduced the serum levels of OVA-specific IgE and IgG2a antibodies. Histologic and flow cytometric studies showed that AICAR inhibited poly (I:C)-induced lung inflammation and the infiltration of CD11b+CD11c+ dendritic cells into the lung. Moreover, AICAR effectively inhibited poly (I:C)-mediated activation of NF-kappaB and the production of TNF-alpha. CONCLUSION: These findings suggest that AICAR may be a novel immunomodulator with promising beneficial effects for the treatment of respiratory viral infection in airway allergic diseases.
Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Asma/tratamiento farmacológico , Asma/prevención & control , Poli I-C/toxicidad , Hipersensibilidad Respiratoria/prevención & control , Ribonucleótidos/farmacología , Aminoimidazol Carboxamida/farmacología , Aminoimidazol Carboxamida/uso terapéutico , Animales , Asma/inducido químicamente , Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Recuento de Células , Línea Celular , Línea Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Células Dendríticas/patología , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Eosinófilos/patología , Femenino , Células HeLa , Humanos , Inmunoglobulinas/sangre , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Linfotoxina-alfa/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Ovalbúmina/inmunología , Especies Reactivas de Oxígeno/metabolismo , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/fisiopatología , Ribonucleótidos/uso terapéuticoRESUMEN
5'-upstream region of the phospholipase C-beta2 gene, 810 bp, was cloned and characterized. S1 nuclease mapping and primer extension analyses revealed that a single transcriptional start site locates at 284 nucleotides upstream from the beginning of translation. The 5-upstream region lacks both TATA motif and typical initiator sequence, but retains GC-rich segment. Two putative regulatory regions, a negative region (-636/-588) and a positive region (-98/ -13) were identified in the upstream region of PLC-beta2 gene. We suggest that the transcription of PLC-beta2 may be regulated by binding of regulatory proteins to the negative and/or positive regulatory regions located in the upstream of the gene.
