Up-regulation of α 1-microglobulin by hemoglobin and reactive oxygen species in hepatoma and blood cell lines

Abstract

α 1-Microglobulin is a 26-kDa glycoprotein synthesized in the liver, secreted to the blood, and rapidly distributed to the extravascular compartment of all tissues. Recent results show that α 1-microglobulin has heme-binding and heme-degrading properties and it has been suggested that the protein is involved in the defense against oxidation by heme and reactive oxygen species. In the present study the influence of hemoglobin and reactive oxygen species (ROS) on the cellular expression of α 1-microglobulin was investigated. Oxy- and methemoglobin, free heme, and Fenton reaction-induced hydroxyl radicals induced a dose-dependent up-regulation of α 1-microglobulin on both mRNA and protein levels in hepatoma cells and an increased secretion of α 1-microglobulin. The up-regulation was reversed by the addition of catalase and ascorbate, and by reacting hemoglobin with cyanide which prevents redox reactions. Furthermore, the blood cell lines U937 and K562 expressed α 1-microglobulin at low levels, and this expression increased up to 11-fold by the addition of hemoglobin. These results suggest that α 1-microglobulin expression is induced by ROS, arising from redox reactions of hemoglobin or from other sources and are consistent with the hypothesis that α 1-microglobulin participates in the defense against oxidation by hemoglobin, heme, and reactive oxygen species.