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 End Stage Renal Disease (ESRD). In the last years inflammation has been greatly reduced but mortality remains high. This study was addressed to assess if low (< 2 pg/ml) circulating levels of interleukin 6 (IL-6) are necessary and sufficient to activate STAT3 transcription factor in human hepatocytes, and if this micro-inflammatory state can be associated with changes in gene expression of some acute phase proteins involved in cardiovascular mortality in ESRD. Human hepatocytes were treated for 24 hours in presence and absence of serum fractions from ESRD patients and healthy subjects with different concentration 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 recombinant (rIL-6) at increasing concentrations was performed. Confocal microscopy and western blotting demonstrated a STAT3 activation associated with IL-6 cell membrane-bound receptors over-expression only in hepatocytes cultured with 1.8 pg/ml of serum IL-6. A linear STAT3 activation and IL-6 receptors expression was also observed after incubation with rIL-6. The hepatocyte treatment with 1.8 pg/ml of serum IL-6 was also associated with 31.6-fold hepcidin gene expression up-regulation and 8.9-fold fetuin-A gene expression down-regulation. 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 differently regulate hepcidin and fetuin-A gene expression.