A nuclear factor for interleukin-6 expression (NF-IL6) and the glucocorticoid receptor synergistically activate transcription of the rat alpha 1-acid glycoprotein gene via direct protein-protein interaction.

Abstract

The acute-phase reaction is accompanied by an increase in a variety of serum proteins, named acute-phase proteins. The synthesis of these proteins is synergistically controlled by glucocorticoids and inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha. Recently, we have cloned nuclear factor-IL-6 (NF-IL6), a transcription factor that activates the IL-6 gene, and have demonstrated its involvement in the expression of acute-phase-protein genes. We report here an analysis of the molecular mechanisms by which inflammatory cytokines and glucocorticoid act synergistically to activate expression of the rat cd-acid glycoprotein (AGP) gene. We found that NF-IL6 and ligand-activated rat glucocorticoid receptor acted synergistically to transactivate the AGP gene and that maximal transcriptional activation of the AGP gene required expression of both intact NF-IL6 and rat glucocorticoid receptor. Surprisingly, however, transcriptional synergism was still observed even when one of the two factors lacked either its DNA-binding or transcriptional-activation function. We present evidence for a direct protein-protein interaction between these two distinct transcription factors and propose that this may be responsible for the synergistic activation of the rat AGP gene.

Anti-inflammatory functions of glucocorticoid-induced genes

“…Composite GC responsive regions have been described in the promoters of tyrosine aminotransferase (Grange et al, 2001;Grange et al, 1989;Roux et al, 1995;Sassi et al, 1998) proliferin (Diamond et al, 1990), α1-acid glycoprotein (Alam et al, 1993;Nishio et al, 1993;Savoldi et al, 1997), the cyclin-dependent kinase inhibitor p21 waf1/cip1 Cram et al, 1998), β1-adrenergic receptor (Tseng et al, 2001), glucose-6-phosphate transporter (Kallwellis-Opara et al, 2003), pyruvate dehydrogenase kinase 4 (Kwon et al, 2004), monoamine oxidase (Manoli et al, 2005;Ou et al, 2006), β-casein (Rosen et al, 1998;Wyszomierski and Rosen, 2001) and others.…”

DNA Binding Specificity of the CCAAT/Enhancer-binding Protein Transcription Factor Family

“…In the cell, many parameters must collaborate to define the function of a given C/EBP-bind- ing site located in chromatin structure, and it is possible that these interact synergistically with other transcription factors. As C/EBP␤ interacts with NF-B-p50 polypeptide and glucocorticoid receptor and C/EBP␣ associates with TFIIB and TATA-binding protein, the differential activity of C/EBP isoforms in vivo may be caused by distinct interactions with other proteins (33)(34)(35). In vivo experiments will be required to clarify the functional specificity of the C/EBP transcription factor family.…”

Cross-talk between glucocorticoid receptor and AP-1

“…Interestingly, the tethering interaction can also lead to synergy, e.g. with AP-1 or NF-kB in certain tissues or cell types (Shemshedini et al, 1991;Maroder et al, 1993;Wang et al, 1997), with Jun homodimers (at a so-called composite element which requires however DNA binding of the GR: Diamond et al, 1990; as well as by pure tethering: Teurich and Angel, 1995), with C/EBP (Nishio et al, 1993) and with Stat-5 (StoÈ cklin et al, 1996).…”