Interleukin-1beta stimulates acute phase response and C-reactive protein synthesis by inducing an NFkappaB- and C/EBPbeta-dependent autocrine interleukin-6 loop.
Cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are involved in acute phase response (APR). C-reactive protein (CRP), the prototype acute phase protein, may represent an important component in the pathogenesis of arteriosclerosis and may also be a target for drug development. Inhibition of CRP synthesis is one potential strategy. Understanding CRP synthesis, however, is a prerequirement for the development of CRP-inhibitors. From studies in hepatoma cell lines, IL-1beta and IL-6 were considered as equal inductors of APR and CRP. We investigated IL-1beta- and IL-6-effects on primary human hepatocytes (PHH) and Hep3B-cells. Kupffer cell contamination in PHH preparations was <3%. In PHH, several APP like CRP, haptoglobin (HP), lipopolysaccharide-binding protein (LBP) or hepcidin (HAMP) were regulated similarly by IL-1beta and IL-6, though signal transduction pathways of these cytokines are different. In Hep3B-cells, APP were regulated exclusively by IL-6. IL-1beta induced IL-6-synthesis in PHH but not in Hep3B-cells. C/EBPbeta-overexpression in Hep3B-cells reconstituted IL-1beta-mediated IL-6/CRP inducibility. In PHH and in C/EBPbeta-overexpressing Hep3B-cells, neutralizing anti-IL-6-antibodies blocked IL-1beta-mediated APR. Inhibition of protein synthesis and NFkappaB-signalling blocked IL-1beta- but not IL-6-mediated CRP-expression in PHH, whereas Janus-Kinase-1-inhibition blocked IL-1beta- and IL-6-mediated APR. IL-1beta induces APR in PHH via an NFkappaB- and C/EBPbeta-dependent autocrine IL-6-loop. These findings partly reconcile the understanding of APR and may help to design a transcriptional suppressor of CRP for the treatment of cardiovascular disease.
Kramer
Frank
F
Sanofi Aventis Pharma GmbH, TD Cardiovascular, 65926 Frankfurt am Main, Germany.
Torzewski
Jan
J
Kamenz
Joachim
J
Veit
Kerstin
K
Hombach
Vinzenz
V
Dedio
Jürgen
J
Ivashchenko
Yuri
Y
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D000210:Acute-Phase Reaction / Q000276:immunology; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000276:immunology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D000209:Acute-Phase Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D002097:C-Reactive Protein