RESUMEN
Ambient particulate matter, including diesel exhaust particles (DEP), promotes the development of allergic disorders. DEP increase oxidative stress and influence human bronchial epithelial cell (HBEC)-dendritic cell interactions via cytokines, including thymic stromal lymphopoietin (TSLP). Upregulation of TSLP results in Th2 responses. Using primary culture HBEC and human myeloid dendritic cell (mDC) cocultures, we show in this study that DEP upregulation of Th2 responses occurred via HBEC-dependent mechanisms that resulted from oxidative stress. Moreover, DEP-treated HBEC and ambient particulate matter-treated HBEC upregulated OX40 ligand (OX40L) and the Notch ligand Jagged-1 mRNA and expression on mDC. Upregulation of OX40L as well as Jagged-1 on mDC required HBEC and did not occur in the presence of N-acetylcysteine. Furthermore, OX40L and Jagged-1 upregulation was inhibited when HBEC expression of TSLP was silenced. Thus, DEP treatment of HBEC targeted two distinct pathways in mDC that were downstream of TSLP expression. Upregulation of OX40L and Jagged-1 by mDC resulted in mDC-driven Th2 responses. These studies expand our understanding of the mechanism by which ambient pollutants alter mucosal immunity and promote disorders such as asthma.
Asunto(s)
Proteínas de Unión al Calcio/biosíntesis , Citocinas/fisiología , Células Dendríticas/inmunología , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Proteínas de la Membrana/biosíntesis , Ligando OX40/biosíntesis , Material Particulado/toxicidad , Mucosa Respiratoria/inmunología , Regulación hacia Arriba/inmunología , Emisiones de Vehículos/toxicidad , Bronquios/citología , Bronquios/efectos de los fármacos , Bronquios/inmunología , Polaridad Celular/efectos de los fármacos , Polaridad Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Humanos , Proteína Jagged-1 , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Células Mieloides/metabolismo , Especies Reactivas de Oxígeno/toxicidad , Receptores Notch/biosíntesis , Mucosa Respiratoria/citología , Mucosa Respiratoria/efectos de los fármacos , Proteínas Serrate-Jagged , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Células del Estroma/efectos de los fármacos , Células del Estroma/inmunología , Células del Estroma/metabolismo , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Timo/citología , Timo/efectos de los fármacos , Timo/inmunología , Regulación hacia Arriba/efectos de los fármacos , Linfopoyetina del Estroma TímicoRESUMEN
RATIONALE: Central alpha(1)- and alpha(2)-adrenoceptors in a number of different brain regions are known to have opposing actions on gross behavioral activity, with the former stimulating and the latter inhibiting activity. Therefore, blockade of alpha(1)-receptors may induce inactivity by leading to unopposed alpha(2) activity. OBJECTIVE: The aim of this study was to test if central blockade of alpha(2)-receptor function restores behavioral activity in alpha(1)-receptor-blocked mice. METHODS: Dose-response studies were undertaken on the effects of alpha(1)- and alpha(2)-agonists and antagonists microinjected into the dorsal pons on gross behavioral activity in a novel cage test. RESULTS: The behavioral inactivity resulting from blockade of alpha(1)-receptors in the pons with the antagonist, terazosin, was reversed by either a low dose of an alpha(2)-antagonist, atipamezole, or a low dose of an alpha(2)-agonist, dexmedetomidine, but was exacerbated by a high dose of the alpha(2)-agonist. CONCLUSION: The results support the hypothesis that blockade of alpha(1)-receptors in the dorsal pons of mice produces inactivity by causing unopposed activity of alpha(2)-receptors. This condition may be relevant to inactive states seen after stress or during depressive illness.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Conducta Animal/efectos de los fármacos , Puente/efectos de los fármacos , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Agonistas alfa-Adrenérgicos/farmacología , Agonistas Adrenérgicos beta/farmacología , Animales , Dexmedetomidina/farmacología , Relación Dosis-Respuesta a Droga , Ambiente , Imidazoles/farmacología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Puente/metabolismo , Prazosina/análogos & derivados , Prazosina/farmacologíaRESUMEN
Previous studies have shown that central alpha1-adrenoceptor activity is necessary, acutely, for gross behavioral activity in response to novel surroundings and various psychostimulants. The present experiment tested whether it is also necessary for the hyperactivity produced by the peptide, orexin A, which is present in several central monoaminergic nuclei. Mice, pretreated intraventricularly with the alpha1-antagonist, terazosin, or the alpha2-antagonist, atipamezole, were given orexin A, intraventricularly (i.v.t.), and videotaped for gross movement and locomotion in the home cage between 30 and 60 min post-infusion. The alpha1-antagonist was found to produce a significant dose-dependent decrease of orexin A-induced activity, which was first seen at the 3 nmol dose and was near total at 30 nmol. The alpha2-antagonist, at 10 nmol, had no effect on the orexin A response. Pharmacological inhibition of the synthesis of epinephrine, a potential neurotransmitter at central motoric alpha1-adrenoceptors, with 2,3-dichloro-alpha-methylbenzylamine also significantly attenuated orexin A-induced hyperactivity. It is concluded that central alpha1-adrenoceptor activity, presumably caused by epinephrine release, is necessary for the gross behavioral activation produced by orexin A.