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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2320.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Increased Expression of the DNA-Binding Cytokine HMGB1 in Human Atherosclerotic Lesions

Role of Activated Macrophages and Cytokines

N. Kalinina; A. Agrotis; Y. Antropova; G. DiVitto; P. Kanellakis; G. Kostolias; O. Ilyinskaya; E. Tararak; A. Bobik

From the Baker Heart Research Institute (N.K., A.A., G.D., P.K., G.K., A.B.), Alfred Hospital, Melbourne, Australia; and the Institute of Experimental Cardiology (N.K., Y.A., O.I., E.T.), Cardiology Research Complex, Moscow, Russia.

Correspondence to Dr Alex. Bobik, Cell Biology Laboratory, Baker Heart Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail alex.bobik{at}baker.edu.au

Objective— Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. High-mobility group box 1 (HMGB1) is a DNA-binding protein, which on release from cells exhibits potent inflammatory actions. We examined its expression in atherosclerotic lesions and regulation by cytokines.

Methods and Results— In atherosclerotic lesions, HMGB1 protein is expressed by endothelial cells, some intimal smooth muscle cells, and macrophages. As atherosclerosis develops and progresses from fatty streaks to fibrofatty lesion, the number of HMGB1-producing macrophages increases markedly. Studies using the THP-1 cell line indicated that HMGB1 mRNA expression could be markedly upregulated by inflammatory cytokines, interferon (IFN)-, tumor necrosis factor (TNF)- and also transforming growth factor (TGF)-ß. IFN-, TNF-, TWEAK, and TGF-ß induced an intracellular redistribution of HMGB1 and stimulated secretion by THP-1 cells and human blood monocytes. Inhibitors of MEK1/MEK2, protein kinase C, and PI-3/Akt, which inhibit lysosomal degranulation and mRNA translation, attenuated cytokine-induced HMGB1 secretion.

Conclusions— Macrophage is the major cell type responsible for HMGB1 production in human atherosclerotic lesions. Inflammatory cytokines and TGF-ß increase HMGB1 expression and secretion by monocyte/macrophages. HMGB1 appears to be a common mediator of inflammation induced by inflammatory cytokines and is likely to contribute to lesion progression and chronic inflammation.

The expression and regulation of high-mobility group box 1 (HMGB1) proinflammatory cytokine in human atherosclerosis were examined. HMGB1 is mostly expressed by macrophages and its expression increases during atherogenesis. Inflammatory cytokines upregulate HMGB1 expression and secretion. HMGB1 is a common mediator of inflammation and may contribute to atherosclerotic lesion progression.

Key Words: high-mobility group box 1 • macrophages • cytokines • inflammation • atherosclerosis

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