Glutathione peroxidase-1 but not-4 is involved in the regulation of cellular 5-lipoxygenase activity in monocytic cells

In contrast to neutrophils or B-lymphocytes, cells of the monocytic lineage like rat macrophages, human peripheral blood monocytes and Mono Mac 6 cell s contain a strong inhibitor of S-lipoxygenase (5-LO) activity, which scave nges hydroperoxides and inhibits 5-LO activity in broken-cell preparations in the absence of exogenously added thiols, Chromatographic purification of the inhibitor from the human monocytic cell line Mono Mac 6 and amino acid sequence analysis revealed that the inhibitory factor is glutathione perox idase-1 (GPx-1), In contrast to the peroxidase activity of GPx-1, 5-LO inhi bition by GPx-1 was supported by beta-mercaptoethanol and there was no abso lute requirement for millimolar concentrations of glutathione or dithiothre itol. These cofactor characteristics suggest that both activities address d istinct catalytic properties of GPx-1. 5-LO inhibition by GPx-1 was not due to direct GPx-5-LO protein-protein interactions, since GPx-1 did not bind to immobilized 5-LO. Interestingly, 5-LO derived from granulocytes was sign ificantly more resistant against GPx-1 inhibition than B-lymphocytic 5-LO, which correlates with the respective cellular 5-LO activities. In summary, the data suggest that, in addition to previously reported phospholipid hydr operoxide glutathione peroxidase (GPx-4), GPx-1 is an efficient inhibitor o f 5-LO even at low thiol concentrations, and is involved in the regulation of cellular 5-LO activity in various cell types.