Repression of transcription factor NF-[kappa]B by glucocorticoids : a molecular mechanism for their anti-inflammatory and immuno-modulatory effects

It has been known since the late 1940s that glucocorticoids (GCs) possess anti-inflammatory activity. Their various uses in the clinic include treatment of, rheumatoid arthritis, asthma and AIM skin diseases and also as means for avoiding rejection during transplantation. Despite the wide usage of GCs, it is only during the last five years that we have started to understand the molecular responsible for this anti-inflammatory activity. The anti-inflammatory action of glucocorticoids has been shown to involve repression of NF-[kappa]B activity. Several different molecular mechanisms have been proposed to be involved in this process. These include retention of NF-[kappa]B in the cytoplasm, glucocorticoid receptor (GR) interference with DNA binding of NF-[kappa]B, induction of I[kappa]B levels and GR inhibition of NF-[kappa]B when NF-[kappa]B is still bound to DNA. The GR is a member of the superfamily of nuclear receptors. In its inactive state it is associated with heat shock proteins. This association maintains the receptor in a conformation that has low affinity for DNA and high affinity for its cognate ligands. After the ligand has bound to the receptor the heat shock proteins dissociate and the receptor changes its conformation, acquiring a high affinity for its DNA binding site. The ligand-activated receptors can both activate and repress transcription from target genes. This gene regulatory function is mediated via direct DNA binding of the receptor and/or by physical contact with other transcription factors or signal mediators. In mammalian cells the family of NF-[kappa]B transcription factors consists of Re1A (p65), NFKB1 (p50), c-Re1, p52 and Re1B. ReIA is the most potent transcriptional activator of the Re1 homology protein family and the principal inducible NF-[kappa]B complex is composed of a heterodimer of ReIA and NFKB1. In the non- activated state this heterodimer is sequestered in the cytoplasm through interaction with the NF-[kappa]B -inhibiting prot