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(Circulation. 2007;116:2043-2052.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon- and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque

Alexander Niessner, MD; Min Sun Shin, PhD; Olga Pryshchep, BS; Jörg J. Goronzy, MD, PhD; Elliot L. Chaikof, MD, PhD; Cornelia M. Weyand, MD, PhD

From the Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of Medicine (A.N., M.S.S., O.P., J.J.G., C.M.W.), and the Department of Surgery (E.L.C.), Emory University School of Medicine, Atlanta, Ga.

Correspondence to Cornelia M. Weyand, MD, PhD, Lowance Center for Human Immunology, Emory University, 101 Woodruff Cir, Atlanta, GA 30322. E-mail cweyand{at}emory.edu

Received February 19, 2007; accepted August 28, 2007.

Background— Interferon (IFN)- is a pluripotent inflammatory cytokine typically induced by viral infections. In rupture-prone atherosclerotic plaques, plasmacytoid dendritic cells produce IFN-. In the present study we explored the contribution of IFN- to inflammation and tissue injury in the plaque microenvironment.

Methods and Results— In 53% of carotid plaques (n=30), CD123⁺ plasmacytoid dendritic cells clustered together with CD11c⁺ myeloid dendritic cells, a distinct dendritic cell subset specialized in sensing danger signals from bacteria and tissue breakdown. Tissue concentrations of IFN- and tumor necrosis factor (TNF)- transcripts were tightly correlated (r=0.76, P<0.001), suggesting a regulatory role of IFN- in TNF- production. Plaque tissue stimulation with CpG ODN, a Toll-like receptor (TLR) 9 ligand, increased IFN- production (57.8±23.7 versus 25.9±8.6 pg/mL; P<0.001), whereas the TLR4 ligand lipopolysaccharide induced TNF- secretion (225.1±3.0 versus 0.7±0.2 pg/mL; P<0.001). Treating plaque tissue with IFN- markedly enhanced lipopolysaccharide-triggered TNF- secretion (559.0±25.9 versus 225.1±3.0 pg/mL; P<0.001). IFN- pretreatment also amplified the effects of lipopolysaccharide on interleukin-12, interleukin-23, and matrix metalloproteinase-9, suggesting that the antiviral cytokine sensitized myeloid dendritic cells and macrophages toward TLR4 ligands. Mechanistic studies demonstrated that IFN- modulated the myeloid dendritic cell response pattern by upregulating TLR4 expression (P<0.001) involving both the STAT (signal transducer and activator of transcription) and the PI(3)K pathway.

Conclusions— In the atherosclerotic plaque, IFN- functions as an inflammatory amplifier. It sensitizes antigen-presenting cells toward pathogen-derived TLR4 ligands by upregulating TLR4 expression and intensifies TNF-, interleukin-12, and matrix metalloproteinase-9 production, all implicated in plaque destabilization. Thus, IFN-–inducing pathogens, even when colonizing distant tissue sites, threaten the stability of inflamed atherosclerotic plaque.

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