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PMID: 1373812 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Molecular and cellular biology ·Vol. 12 ·No. 5 ·1992-05-00 ·Pages 2282-94

Hocke GM, Barry D, Fey GH

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.

MeSH Terms
Animals Base Sequence Carcinoma, Hepatocellular Cell Line Cell Nucleus/metabolism DNA-Binding Proteins/isolation & purification,metabolism Drug Synergism Genes, Regulator/drug effects Glucocorticoids/pharmacology Humans Interleukin-6/pharmacology Kinetics Liver/physiology Liver Neoplasms Molecular Sequence Data Molecular Weight Multiple Myeloma Oligonucleotide Probes Plasmids Rats Restriction Mapping Transcription Factors/metabolism Transfection alpha-Macroglobulins/genetics
Chemicals
DNA-Binding Proteins Glucocorticoids Interleukin-6 Oligonucleotide Probes Transcription Factors alpha-Macroglobulins
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Hocke G M
Department of Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037.
Barry D
Fey G H
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.12.5.2282-2294.1992
Published
1992-05-00
Pages
2282-94
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC364400
Subset
IM
Grants
NIAID NIH HHS · AI22166 · United States
NIAID NIH HHS · AI23351 · United States
External Links
PubMed source DOI: 10.1128/mcb.12.5.2282-2294.1992 PMC Full Text View journal details
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