CXCL16 Is a Marker of Inflammation, Atherosclerosis, and Acute Coronary Syndromes in Humans
Michael Lehrke, MD*, ,
Segan C. Millington, BS*,
Martina Lefterova, BS*,
Reshmaal Gomes Cumaranatunge, MD ,
Philippe Szapary, MD, MSCE, ,
Robert Wilensky, MD, FACC,
Daniel J. Rader, MD*,,,
Mitchell A. Lazar, MD, PhD* and
Muredach P. Reilly, MB, MSCE*,,,*
* Institute of Diabetes, Obesity, and Metabolism
Cardiovascular Institute
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Department of Gastroenterology, Endocrinology, and Metabolism, Ludwig-Maximilians University of Munich, Munich, Germany
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Figure 1 Human Endotoxemia Induces CXCL16 In Vivo
(A) Whole-blood CXCL16 and tumor necrosis factor (TNF)-alpha messenger ribonucleic acid (mRNA) and (B) plasma protein levels were measured serially for 20 h before and 24 h after intravenous lipopolysaccharide (LPS) (3 ng/kg) in 6 healthy volunteers. Repeated-measures ANOVA revealed significant effects on CXCL16 mRNA (F = 6.89, p < 0.001) and sol-CXCL16 (F = 6.15, p < 0.001) levels.
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Figure 2 Inhibition of CXCL16 Induction by Anti-Inflammatory Drugs
Down-regulation of (A) CXCL16 mRNA (F = 19.4, p = 0.001) and (B) CXCL16 protein secretion (F = 71.9, p < 0.001) by aspirin (ASA) in human macrophages. Cells were pre-treated with aspirin for 2 h and then for 24 h with LPS (1 µg/ml). **p < 0.01, ***p < 0.001 by t test compared to LPS-induced CXCL16 levels. (C) Down-regulation of CXCL16 mRNA in human macrophages by the nuclear factor-kappa-B inhibitor SN50 (t test p = 0.002). Cells were pretreated with SN50 or control peptide at 100 µg/ml for 2 h, then for 24 h with LPS (1 µg/ml). (D) Induction of CXCL16 in human macrophages by adenovirus over-expression (24 h) of activated I-kappa-B kinase compared to control virus (*t test p = 0.03). Results of representative experiments with triplicate samples are expressed as mean ± (SEM). GFP = green fluorescent protein; other abbreviations as in Figure 1.
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Figure 3 Inhibition of Sol-CXCL16 by Rosiglitazone In Vitro and In Vivo
(A) Down-regulation of sol-CXCL16 protein by rosiglitazone (Rosi) in mouse macrophages (*F = 38.4, p = 0.005; p < 0.01 rosiglitazone/LPS versus LPS alone). Cells were pretreated with rosiglitazone (1 µM x 24 h) and then with LPS (1 µg/ml x 24 h). (B) LPS-dependent induction of plasma sol-CXCL16 is blocked by rosiglitazone in mice (F = 8.83, p = 0.01). LDLR–/– mice (8 per group) were treated for 7 days with rosiglitazone (30 mg/kg) or vehicle and injected intraperitoneally with LPS (200 ng/g). Abbreviations as in Figure 1.
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