Hypoxia–reoxygenation enhances interleukin-8 production from U937 human monocytic cells

Abstract

Hypoxia–reoxygenation (H/R) occurs in both inflammatory spots and tumor tissues, sites in which damage is amplified either acutely or chronically through the infiltration of inflammatory cells. Interleukin-8 (IL-8) is a cytokine with chemotactic and angiogenic properties. This study was designed to investigate the effects of H/R on IL-8 production in the U937 human monocytic cell line. Two hours of hypoxia followed by 4 h of reoxygenation induced a significant increase in IL-8 protein production and IL-8 mRNA expression in U937 cells. Pretreatment with proteasome inhibitor (PSI), a peptide aldehyde known to inhibit the chymotrypsin-like activity of the 26S proteasome specifically, suppressed IL-8 protein production and IL-8 mRNA expression induced by H/R. The production of IL-8 protein induced by H/R was decreased by pioglitazone and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), which have been identified as peroxisome proliferator-activated receptorγ (PPAR-γ) ligands. Moreover, transfection of U937 cells with a dominant negative IκBαexpression vector (IκBαM) decreased IL-8 protein production induced by H/R. These results suggest that NF-κB and PPAR-γ regulate H/R-stimulated IL-8 production in U937 cells.