Synergistic action of interleukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat alpha 2 macroglobulin gene.

Abstract

One class of genes coding for the acute-phase proteins (acute-phase genes) is induced by interleukin 6 (IL-6) through the human transcription factor NF-IL-6 and its rat homolog IL-6-DBP/LAP. A second class, represented by the rat alpha 2 macroglobulin gene, utilizes a different IL-6 response element (IL-6-RE) and different DNA-binding proteins interacting with this element, the so-called IL-6-RE binding proteins (IL-6 RE-BPs). Human Hep3B and HepG2 hepatoma, U266 myeloma, and CESS lymphoblastoid cells contain IL-6 RE-BPs that form complexes, with the IL-6-RE, with gel mobilities indistinguishable from those of the corresponding complexes of rat liver cells. The ability to form these complexes was induced by IL-6 in human hepatoma cells with a maximum reached after 4 h and required ongoing protein synthesis. Multiple copies of an 18-bp element containing the IL-6-RE core were sufficient to confer both induction by IL-6 and a synergistic induction by IL-6 plus glucocorticoids to minimal promoters. The synergism was blocked by the receptor antagonist RU486 and thus was dependent on the glucocorticoid receptor (GR). However, the 18-bp element contained no consensus GR-binding site, and recombinant GR did not bind at this sequence. Therefore, the synergism was probably achieved by an indirect effect of a glucocorticoid-activated intermediate gene on the IL-6 RE-BPs. The rat IL-6 RE-BP had a molecular weight of 102 +/- 10 kDa and was thus distinct from NF-IL-6 and IL-6-DBP/LAP. Therefore, IL-6 must activate two different classes of liver acute-phase genes through at least two different nuclear DNA-binding proteins: NF-IL-6/IL-6-DBP/LAP and the IL-6 RE-BP.

IL-6 downregulates transcription of NTPDase2 via specific promoter elements

“…The same band was also seen with the α 2 -macroglobulin-specific probe (data not shown). The bands obtained are similar to the data previously published with a typical IL-6 RE (19). The specificity of the binding was confirmed by competition assays.…”

“…In this study we have shown that PF express gp130, providing a molecular basis for IL-6 responsiveness. IL-6-sensitive changes in transcription are mediated via actions of specific promoter IL-6 REs (16,19). Although the intermediate steps coupling IL-6 receptor activation and IL-6 REs are unclear, a set of IL-6 RE binding proteins have been identified, which mediate IL-6-sensitive induction of α 2 -macroglobulin (19).…”

Two distinct pathways can control expression of the gene encoding the Drosophila antimicrobial peptide metchnikowin

“…Our analysis also revealed other consensus nucleotide sequence motifs in the metchnikowin promoter, corresponding to mammalian NF-IL6 response elements (Hocke et al, 1992), GATA sites (Orkin, 1992), and interferon consensus response elements (Figure 4(c)). …”

“…In addition to Rel sites, the metchnikowin promoter contains sequence motifs homologous to cisacting regulatory elements binding the mammalian transcription factors GATA (Orkin, 1992), NF-IL6 (Hocke et al, 1992), as well as several GGAAANN sequence motifs present in the interferon consensus response elements of mammalian interferoninduced genes . In mammals, cooperative interaction of NF-kB with multiple transcription factors is well documented (Siebenlist et al, 1994).…”

The synthesis of α2‐macroglobulin by rat mammary myoepithelial cells is regulated by synergism between glucocorticoids and cytokines

“…interleukin-1 (IL-l), IL-6 and tumour necrosis factor-a (TNFa) [6,7& a,-Macroglobulin synthesis is primarily induced by IL-6 and is considerably further enhanced by glucocorticoids in vivo and in vitro [8,9]. The 5' flanking region of the rat a2-macroglobulin gene contains both IL-6 and glucocorticoid response elements [lO,l 11.…”