A translational approach to micro-inflammation in end-stage renal disease: molecular effects of low levels of interleukin-6

• Published in: Clinical science (1979) Vol. 119; no. 4; pp. 163 - 174
• Main Authors: Memoli, Bruno, Salerno, Simona, Procino, Alfredo, Postiglione, Loredana, Morelli, Sabrina, Sirico, Maria Luisa, Giordano, Francesca, Ricciardone, Margherita, Drioli, Enrico, Andreucci, Vittorio E., de Bartolo, Loredana
• Format: Journal Article
• Language: English
• Published: London Portland Press 14.05.2010
• Subjects: Adult; alpha-2-HS-Glycoprotein; Antimicrobial Cationic Peptides - biosynthesis; Antimicrobial Cationic Peptides - genetics; Biological and medical sciences; Blood Proteins - biosynthesis; Blood Proteins - genetics; C-Reactive Protein - analysis; Cells, Cultured; Cytokine Receptor gp130 - metabolism; Cytokines - blood; Female; Gene Expression Regulation; General aspects; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepcidins; Humans; Inflammation - blood; Inflammation - etiology; Interleukin-6 - blood; Interleukin-6 - pharmacology; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - therapy; Male; Medical sciences; Microscopy, Confocal; Middle Aged; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Receptors, Interleukin-6 - metabolism; Recombinant Proteins - pharmacology; Renal Dialysis; Renal failure; STAT3 Transcription Factor - metabolism; Kidney disease; Human; Urinary system disease; Chronic renal failure; Cytokine; Terminal stage; Inflammation; micro-inflammation; Genetic translation; interleukin-6 (IL-6); Interleukin 6; Medicine; Signal transduction; Activator; end-stage renal disease (ESRD); signal transducer and activator of transcription 3 (STAT3); Transcription factor STAT3; Renal failure; fetuin-A; Fetuin; Hepcidin
• ISSN: 0143-5221; 1470-8736; 1470-8736
• DOI: 10.1042/CS20090634

Inflammation plays a key role in the progression of cardiovascular disease, the leading cause of mortality in ESRD (end-stage renal disease). Over recent years, inflammation has been greatly reduced with treatment, but mortality remains high. The aim of the present study was to assess whether low (<2 pg/ml) circulating levels of IL-6 (interleukin-6) are necessary and sufficient to activate the transcription factor STAT3 (signal transducer and activator of transcription 3) in human hepatocytes, and if this micro-inflammatory state was associated with changes in gene expression of some acute-phase proteins involved in cardiovascular mortality in ESRD. Human hepatocytes were treated for 24 h in the presence and absence of serum fractions from ESRD patients and healthy subjects with different concentrations of IL-6. The specific role of the cytokine was also evaluated by cell experiments with serum containing blocked IL-6. Furthermore, a comparison of the effects of IL-6 from patient serum and rIL-6 (recombinant IL-6) at increasing concentrations was performed. Confocal microscopy and Western blotting demonstrated that STAT3 activation was associated with IL-6 cell-membrane-bound receptor overexpression only in hepatocytes cultured with 1.8 pg/ml serum IL-6. A linear activation of STAT3 and IL-6 receptor expression was also observed after incubation with rIL-6. Treatment of hepatocytes with 1.8 pg/ml serum IL-6 was also associated with a 31.6-fold up-regulation of hepcidin gene expression and a 8.9-fold down-regulation of fetuin-A gene expression. In conclusion, these results demonstrated that low (<2 pg/ml) circulating levels of IL-6, as present in non-inflamed ESRD patients, are sufficient to activate some inflammatory pathways and can differentially regulate hepcidin and fetuin-A gene expression.