HMGB1 expression and secretion is increased via TWEAK-Fn14 interaction in atherosclerotic plaques and in cultured monocytes

Abstract

Objective: High-mobility group box 1 (HMGB1), a DNA-binding cytokine expressed mainly by macrophages, contributes to lesion progression and chronic inflammation within atherosclerotic plaque. Recently, it has been suggested that different cytokines could regulate HMGB1 expression in monocytes. Now, we have analyzed the effect of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) on HMGB1 expression both in vivo and in vitro. Methods and Results: Expression of TWEAK and its receptor fibroblast growth factor–inducible 14 (Fn14) was positively correlated with HMGB1 in human carotid atherosclerotic plaques. TWEAK increased HMGB1 mRNA expression and protein secretion in human acute monocytic leukemia cell line cultured monocytes. TWEAKmediated HMGB1 increase was only observed in M1 macrophages but not in M2 ones. These effects were reversed using blocking antiFn14 antibody or nuclear factorkappa B and phosphotidylinositol3 kinase inhibitors. TWEAK also increased monocyte chemoattractant protein1 secretion in human acute monocytic leukemia cell line cells, an effect blocked with an HMGB1 small interfering RNA. Systemic TWEAK injection in ApoE−/− mice increased HMGB1 protein expression in the aortic root and mRNA expression in total aorta of ApoE−/− mice. Conversely, TWEAKblocking antibodies diminished HMGB1 protein and mRNA expression compared with IgGtreated mice. Conclusions: Our results indicate that TWEAK can regulate expression and secretion of HMGB1 in monocytes/ macrophages, participating in the inflammatory response associated with atherosclerotic plaque development.