RESUMEN
The enzyme type 2 deiodinase (D2) is a major determinant of T3 production in the central nervous system. It is highly expressed in tanycytes, a specialized cell type lining the wall of the third ventricle. During acute inflammation, the expression of D2 in tanycytes is up-regulated by a mechanism that is poorly understood at present, but we hypothesized that cJun N-terminal kinase 1 (JNK1) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) (the 65 kD subunit of NFκB) inflammatory signal transduction pathways are involved. In a mouse model for acute inflammation, we studied the effects of lipopolysaccharide (LPS) on mRNA expression of D2, JNK1, and RelA in the periventricular area (PE) and the arcuate nucleus-median eminence of the hypothalamus. We next investigated LPS-induced D2 expression in primary tanycyte cell cultures. In the PE, the expression of D2 was increased by LPS. In the arcuate nucleus, but not in the PE, we found increased RelA mRNA expression. Likewise, LPS increased D2 and RelA mRNA expression in primary tanycyte cell cultures, whereas JNK1 mRNA expression did not change. Phosphorylation of RelA and JNK1 was increased in tanycyte cell cultures 15-60 minutes after LPS stimulation, confirming activation of these pathways. Finally, inhibition of RelA with the chemical inhibitors sulfasalazine and 4-Methyl-N¹-(3-phenylpropyl)benzene-1,2-diamine (JSH-23) in tanycyte cell cultures prevented the LPS-induced D2 increase. We conclude that NFκB signaling is essential for the up-regulation of D2 in tanycytes during inflammation.
Asunto(s)
Endotoxinas/toxicidad , Inducción Enzimática/efectos de los fármacos , Células Ependimogliales/efectos de los fármacos , Yoduro Peroxidasa/biosíntesis , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Transducción de Señal/efectos de los fármacos , Animales , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/inmunología , Núcleo Arqueado del Hipotálamo/metabolismo , Células Cultivadas , Células Ependimogliales/citología , Células Ependimogliales/inmunología , Células Ependimogliales/metabolismo , Femenino , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Masculino , Eminencia Media/citología , Eminencia Media/efectos de los fármacos , Eminencia Media/inmunología , Eminencia Media/metabolismo , Ratones , Ratones de la Cepa 129 , Núcleos Talámicos de la Línea Media/citología , Núcleos Talámicos de la Línea Media/efectos de los fármacos , Núcleos Talámicos de la Línea Media/inmunología , Núcleos Talámicos de la Línea Media/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Ratas , Ratas Wistar , Factor de Transcripción ReIA/biosíntesis , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Yodotironina Deyodinasa Tipo IIRESUMEN
The hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic and/or extrahypothalamic regions is believed to contribute to the pathophysiology of major depression in an experimental animal chronically exposed to stress. In the present study, we examined the effects of chronic variable stress (CVS) and novel stress (footshock) on the CRH immunoreactivity in the hypothalamic paraventricular nucleus (PVN) and subdivision of PVN, and the extrahypothalamic bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA). We observed a significant reduction in CRH levels in the whole PVN, lateral parvocellular part of PVN, BNST and CeA 24 hours after the last stressor of CVS for 13 days. A novel stressor after CVS caused a marked increase in CRH levels in these four regions, followed a further reduction observed 24 hours later. Since the CVS-induced modulation of CRH levels are consistent with an alteration of tyrosine hydroxylase levels in the locus coeruleus, CRH-norepinephrine (NE) interaction in the terminal projection of forebrain NE systems, PVN, BNST and CeA where NE stimulates CRII release, might contribute to the bi-directional change in CRH. The CVS-induced bi-directional changes in CRH of PVN, BNST and CeA might play a role in the formation of the pathophysiology of major depressive disorders.