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

作者：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

来源：Clinical Science, 2010, 119(3-4): 163-174.

DOI：10.1042/CS20090634

• end-stage renal disease (ESRD)
• fetuin-A
• hepcidin
• interleukin-6 (IL-6)
• micro-inflammation
• signal transducer and activator of transcription 3 (STAT3)

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.

• 出版日期2010-8