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

Abstract

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.

Dietary glycotoxins induce RAGE and VEGF up-regulation in the retina of normal rats

“…Previous studies support this finding since they demonstrate that AGEs per se are proinflammatory mediators that directly stimulate hepatic CRP production (Li et al, 2007;Yoshida et al, 2006aYoshida et al, , 2006bZhong et al, 2006). Interestingly, in the present study, elevated CRP levels were strongly correlated with increased AGEs, RAGE and VEGF immunoreactivity in the retina and uveal tissues confirming the interplay of these molecules in the induction of inflammatory processes.…”

Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes

“…In the another experiment, the cells were pretreated with anti-IL-6 or/and anti-IL-1β neutralizing antibodies (5 μg/ml) for 1 h prior to Ang II (10 -6 M) stimulation for 24 h [19]. Finally, CRP was assayed by Western blot.…”

Advanced glycation end products and arterial stiffness in patients with diabetic nephropathy and patients with chronic kidney disease without diabetes

“…It was also shown that AGEs upregulate CRP synthesis by human hepatocytes through stimulation of monocyte interleukin 6 and interleukin 1β production. 37 In hemodialyzed patients, the tissue level of AGEs was an independent determinant of the hsCRP level. 38 In our study, there was no relationship between plasma AGE levels and hsCRP.…”