Carbonyl compounds methylglyoxal and glyoxal affect interleukin-8 secretion in intestinal cells by superoxide anion generation and activation of MAPK p38

The carbonyl compounds methylglyoxal (MG) and glyoxal (GL) are reactive intermediates of glucose degradation pathways and capable of inducing cellular damage. Although immune-stimulating activity has been investigated in endothelial cells, little is known about the signaling pathways of cytokine induction of these compounds in the intestine. Hence, we investigated the impact of mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB) on IL-8 production by human intestinal cells (Caco-2 and HT-29) after stimulation by MG and GL. Both compounds induced a dose-dependent enhancement of IL-8 secretion in human intestinal cells. MAPK p38 and extracellular signal-regulated kinase (ERK) were phosphorylated in these cells after having been stimulated by MG and GL. Furthermore, inhibitors of MAPK p38 (SB 203580 and 239063), ERK1/2 (PD 98059) and NF-κB activation (SM-7368 and SC-514) reduced IL-8 secretion. The most important mechanism by which MG and GL induced IL-8 secretion was the generation of superoxide anions which was confirmed by the inhibition of the cytosolic NADPH Oxidase with diphenyl iodonium (DPI) or by application of superoxide dismutase (SOD). Our data suggest that multiple pathways were simultaneously activated; however, superoxide dependent MAPK p38 activation seems to be the most dominant pathway for IL-8 secretion in intestinal cells.