Glucocorticoids in the regulation of transcription factors that control cytokine synthesis

A LIBERMAN, J DRUKER, M PERONE,F HOLSBOER, E ARZT

Cytokine & Growth Factor Reviews

Año: 2006

There are different levels of interaction between GCs and cytokines, starting with selective regulation (induction or repression) of the expression of cytokine receptor genes. Another level implies the cross-talk between the activated glucocorticoid receptor (GR) and transcription factors (TF) which are implicated in the regulation of cytokine synthesis and function which is known to take place by a number of diverse mechanisms. GR was initially demonstrated to mediate transcriptional activation of the murine mammary tumor virus (MMTV) gene by binding as a dimer to a consensus response element, the GRE. Subsequently, however, the array of mechanisms utilized by GR in controlling gene expression has expanded, and in particular, details of transcriptional repression by GR have emerged. These mechanisms involve both DNA binding, the demonstration of the negative GRE (nGRE), the recruitment of either coactivator or co-repressor complexes to a common subunit, the ability to sequester non-DNA-bound proteins, and the regulation of kinase activity. It is now clear that some of these systems may operate in conjunction with one another, thereby imparting both variability and complexity of transcriptional regulation upon target cytokine promoters. A further level of interaction involves mutual regulation by the ubiquitin-proteasome and sumoylation systems which regulate GR transactivation modifying receptor trafficking and turnover. Many other posttranslational modifications such as acetylation, methylation, phosphorylation, and ubiquitylation and novel proteins such as specific components of chromatin remodeling machines may have a role in maintaining the turnover of the GR and associated factors at active sites of transcription modifying gene expression. In this article we will review the different levels of regulatory interaction between GCs and cytokines revising the molecular mechanisms implicated and the functional concequences.