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PMID: 9185517 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein.

The Journal of clinical investigation ·Vol. 99 ·No. 12 ·1997-06-15 ·Pages 2930-40

Gabay C, Smith MF, Eidlen D, Arend WP

Abstract

Interleukin 1 receptor antagonist (IL-1Ra) levels are elevated in the blood of patients with a variety of infectious, immune, or traumatic conditions. To examine whether IL1Ra is produced by liver cells with characteristics resembling an acute-phase protein, human primary hepatocytes isolated from liver biopsies and HepG2 hepatoma cells were stimulated with IL-1beta, IL-6, and TNFalpha. IL-1Ra was present in the supernatants of both cells, with production significantly enhanced by IL-1beta, and by the combination of IL-1beta and IL-6. The term IL-1Ra refers to two different proteins encoded by the same gene, but generated by alternative splicing of two different first exons. One isoform is secreted (17-kD sIL-1Ra), and the other isoform remains in the cytoplasm (18-kD icIL-1Ra). By Western blot analysis, the supernatants of human hepatoma (HepG2) cells contained only sIL-1Ra, whereas the lysates contained a novel smaller molecular mass isoform of 16 kD. RT-PCR and ribonuclease protection assay with RNA from HepG2 cells showed that only sIL-1Ra mRNA was expressed, and confirmed the inducing effect of IL-1beta and IL-6. Transfection studies were performed using constructs containing the promoters of either sIL-1Ra or icIL-1Ra coupled to the luciferase reporter gene. The sIL-1Ra promoter was active in HepG2 cells stimulated by IL-1beta and/or IL-6, whereas the icIL-1Ra promoter was inactive. Mutation of binding sites for transcription factors NF-kappaB and/or C/EBP within the proximal sIL-1Ra promoter led to significant decreases in response to IL-1beta and IL-6 in comparison to the wild-type promoter. Electromobility gel shift assays confirmed the presence of NF-kappaB and C/EBP binding sites within the sIL-1Ra promoter, and indicated a significant increase in the binding activities of nuclear proteins from HepG2 cells treated with IL-1beta and IL-6. In summary, sIL-1Ra, but not icIL-1Ra, is produced by hepatocytes, and is regulated by proinflammatory cytokines as an acute-phase protein. In addition, NF-kappaB and C/EBP family members are likely to play important roles in the full expression of IL-1Ra by hepatocytes during inflammatory conditions.

MeSH Terms
Acute-Phase Proteins Binding Sites Carcinoma, Hepatocellular Cells, Cultured DNA/chemistry,metabolism DNA-Binding Proteins/metabolism Electrophoresis Humans Interleukin 1 Receptor Antagonist Protein Interleukin-1/pharmacology Interleukin-6/pharmacology Liver/metabolism Liver Neoplasms NF-kappa B/metabolism Polymerase Chain Reaction RNA, Messenger/analysis Sialoglycoproteins/biosynthesis,genetics Transfection Tumor Cells, Cultured Tumor Necrosis Factor-alpha/pharmacology
Chemicals
Acute-Phase Proteins DNA-Binding Proteins IL1RN protein, human Interleukin 1 Receptor Antagonist Protein Interleukin-1 Interleukin-6 NF-kappa B RNA, Messenger Sialoglycoproteins Tumor Necrosis Factor-alpha DNA
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Gabay C
Division of Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. gabay_c@defiance.uchsc.edu
Smith M F
Eidlen D
Arend W P
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI119488
Email
gabay_c@defiance.uchsc.edu
Published
1997-06-15
Pages
2930-40
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC508145
Subset
IM
Grants
NIAID NIH HHS · AI-34358 · United States
NIAMS NIH HHS · AR-40135 · United States
Corrections
CommentIn
PMID: 9185500
External Links
PubMed source DOI: 10.1172/JCI119488 PMC Full Text View journal details
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