Methotrexate regulates the expression of glucocorticoid receptor alpha and beta isoforms in normal human peripheral mononuclear cells and human lymphocyte cell lines in vitro.
Mol Immunol
; 44(8): 2115-23, 2007 Mar.
Article
em En
| MEDLINE
| ID: mdl-17118450
MTX is an effective therapy for autoimmune-inflammatory diseases. The mechanisms that mediate these actions are not completely clear. It is accepted that many of these effects are mediated through the release of adenosine with the activation of the adenosine receptor A2. MTX is used as a steroid sparing agent. An improved in vitro GC cell sensitivity in GC insensitive asthma patients has been demonstrated after MTX treatment. Most GC actions are mediated by the GCR. The effect of MTX on GCRs expression has not been previously evaluated. Therefore, we evaluate if MTX regulates the expression of glucocorticoid receptors, increasing the expression of the active receptor (GCR alpha) and/or decreasing the expression of the dominant negative receptor (GCR beta). We show that MTX increases the mRNA and protein levels of GCR alpha and decreases or leaves unchanged the protein expression of the GCR beta in CEM cells in culture. This effect was also observed in other lymphocytes (Jurkat and Raji) and in PBMNC from healthy volunteers. We also show that upon MTX treatment PBMC from normal volunteers exhibit a higher sensitivity to DEX inhibition on LPS-induced TNF alpha release. To explore if these actions are mediated by adenosine through the adenosine receptor A2 we evaluate the effect of adenosine on the GCRs expression and the effect of an A2 receptor blocker (DMPX) on MTX effects on GCRs expression. Our results show that adenosine does not mimic and DMPX can enhance MTX effects on these receptors. We conclude that MTX increases the GCR alpha/GCR beta ratio of expression in lymphocytes which could mediate its previously reported effects in improving cell glucocorticoid sensitivity. These actions are not mediated by the adenosine receptor A2.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos
/
Receptores de Glucocorticoides
/
Regulação da Expressão Gênica
/
Metotrexato
/
Imunossupressores
Limite:
Humans
Idioma:
En
Revista:
Mol Immunol
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Chile
País de publicação:
Reino Unido