Advanced Glycation End Products Upregulate C-reactive Protein Synthesis by Human Hepatocytes Through Stimulation of Monocyte IL-6 and IL-1β Production

Patients with chronic renal failure are characterized by increased plasma levels of C-reactive protein (CRP) and advanced glycation end products (AGE). AGE have been identified as a class of proinflammator mediators. To investigate whether AGE can stimulate hepatocytes to produce CRP, primary human fetal hepatocytes (HFH) were incubated with AGE-modified human serum albumin (AGE-HSA) or conditioned medium from AGE-HSA-stimulated monocytes (AGE-MCM). CRP concentrations in the supernatants were determined by an ELISA and CRP mRNA levels were determined by a quantitative RT-PCR. Exposure of HFH with AGE-HSA for 12-72 h did not change CRP concentrations in the supernatants. CRP protein and mRNA expression were significantly upregulated in a time- and dose-dependent manner when HFH were incubated with AGE-MCM. This stimulating effect was partially inhibited when AGE-MCM were preincubated with antibodies against interleukin-6 (anti-IL-6), interleukin-1β (anti-IL-1β), or soluble IL-1 receptor and was completely inhibited when AGE-MCM were preincubated with anti-IL-6 and anti-IL-1β simultaneously. The inhibiting effect did not occur when AGE-MCM was preincubated with antibody of tumour necrosis factor-α (anti-TNF-α) and soluble TNF receptor. Exposure of HFH with exogenous IL-6 and IL-1β, at the same concentrations as contained in AGE-MCM, also increased CRP production, but exogenous TNF-α had no effect. These results suggest that AGE cannot directly stimulate hepatocytes to produce CRP, but rather indirectly enhance CRP expression via stimulation of IL-6 and IL-1β production by human monocytes.