A translational approach to micro-inflammation in end-stage renal disease: molecular effects of low levels of interleukin-6.
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.
Memoli
Bruno
B
Department of Nephrology, University Federico II of Naples, 80131 Naples, Italy.
Salerno
Simona
S
Procino
Alfredo
A
Postiglione
Loredana
L
Morelli
Sabrina
S
Sirico
Maria Luisa
ML
Giordano
Francesca
F
Ricciardone
Margherita
M
Drioli
Enrico
E
Andreucci
Vittorio E
VE
Bartoli
Loredana De
LD
D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics; D002097:C-Reactive Protein / Q000032:analysis; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000209:etiology*; D015850:Interleukin-6 / Q000097:blood* / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000628:therapy; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D006435:Renal Dialysis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D016207:Cytokines; C578702:HAMP protein, human; D064451:Hepcidins; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D060749:alpha-2-HS-Glycoprotein; D050822:Cytokine Receptor gp130; D002097:C-Reactive Protein