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Endothelial activation and induction of monocyte adhesion by nontransferrin-bound iron present in human sera

Nontransferrin-bound iron (NTBI) has been detected in iron overload diseases. This form of iron may exert pro-oxidant effects and modulate cellular function and inflammatory response. The present study has aimed to investigate the effects of serum NTBI on monocyte adherence to endothelium.

Measured by a recently developed high-throughput fluorescence-based assay, serum NTBI was found to be higher in both homozygotes of HFE C282Y mutation of hereditary hemochromatosis (7.9 +/- 0.6 iM, n=9, P<0.001) and heterozygotes (4.0±0.5 ìM, n=8, P<0.001), compared with controls (1.6 +/-0.2 iM, n=21). The effects of these sera on monocyte adhesion and endothelial activation were examined. Adhesion of normal human monocytes to C282Y homozygote- and heterozygote-serum-treated human umbilical vein endothelial cells was higher (25.0±0.9 and 22.1 +/-0.7%, respectively) compared with controls (17.6 +/- 0.5%, both P<0.001). For the three groups combined, the expression of adhesion molecules, ICAM-1, VCAM-1, and E-selectin, was positively correlated to NTBI levels but not to the inflammatory marker C-reactive protein. Furthermore, accumulation of intracellular labile iron and oxidative radicals within the cells due to NTBI was evidenced. Finally, counteraction of NTBI-induced endothelial activation was observed using iron chelators.

Conclusion: These findings therefore identify a physiological function of NTBI in monocyte-endothelial interactions that may also contribute to the development of atherosclerosis and neurodegenerative diseases.

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