RESUMEN
The analysis of the molecular basis of autoimmune diseases is currently under intense investigation. The identification of novel mechanisms underlying the pathogenesis of these diseases generates the possibility for the development of new therapeutic agents. In this review we summarize the results leading to novel insights concerning the molecular processes involved in the pathogenesis of rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis and diabetes type 1. We focus on the role of transcription factors such as nuclear factor kappa B, activator protein 1, peroxisome proliferator-activated receptor, vitamin D receptor and the glucocorticoid receptor that mediate pro- and anti-inflammatory effects and therefore represent direct or indirect targets for therapeutic intervention.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Factores de Transcripción , Factores de Transcripción/fisiología , Animales , Enfermedades Autoinmunes/terapia , Humanos , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To study a possible relationship between expression of the transcription factor glucocorticoid receptor (GR), which mediates antiinflammatory effects, and the transcription factor p50, which mediates proinflammatory effects, in peripheral blood mononuclear cells (PBMC) of patients with rheumatoid arthritis (RA). METHODS: Expression analysis of GR and nuclear factor-kB subunit p50 in PBMC was performed by semiquantitative immunoblotting. RESULTS: GR and p50 expression in PBMC were significantly increased in patients with RA who had never received corticosteroids. In contrast, GR density is decreased in glucocorticoid treated RA patients. In addition, a dependency between increased GR expression and increased p50 expression was found. CONCLUSION: The pathogenesis of RA is not reflected in diminished GR expression but rather in an increased expression level of GR, as well as increased p50 expression in PBMC. Corticosteroids as the major therapeutic drugs result in a reduction of these increased GR and p50 expression levels.
Asunto(s)
Artritis Reumatoide/metabolismo , Leucocitos Mononucleares/metabolismo , FN-kappa B/biosíntesis , Receptores de Glucocorticoides/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/tratamiento farmacológico , Femenino , Humanos , Immunoblotting , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Subunidad p50 de NF-kappa B , Prednisolona/farmacología , Prednisolona/uso terapéuticoRESUMEN
The glucocorticoid receptor (GR) is a ligand-inducible transcription factor which controls the expression of several genes. Its cognate ligand, the glucocorticoids, induces receptor activation by binding to the cytoplasmic located receptor, ultimately leading to translocation of the receptor/hormone complex into the nucleus and the regulation of gene activity. Because glucocorticoids are widely used for suppression of inflammation in rheumatoid arthritis (RA), we investigated whether the expression level of GR is correlated with RA. We designed a study to detect the total amount of GR in lymphocytes of untreated RA patients, glucocorticoid-treated RA patients, and healthy controls. We observed a significant change in the expression levels of GR. Untreated RA patients exhibited a significantly higher amount of GR than the healthy controls, whereas glucocorticoid-treated RA patients showed a strongly decreased receptor density. These results seem to reflect a functional dysregulation of the HPA axis and may lead to a better understanding of the pathogenesis of RA.