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An Inflammatory Pathway of IFN- Production in Coronary Atherosclerosis¹

Hooman Ranjbaran^2,*, Seth I. Sokol^2,, Amy Gallo^*, Raymond E. Eid^*, Alexander O. Iakimov^*, Alessio D’Alessio, John R. Kapoor, Shamsuddin Akhtar, Christopher J. Howes, Mihaela Aslan, Steven Pfau, Jordan S. Pober and George Tellides^3,*

^* Department of Surgery, Department of Medicine, Department of Pathology, and Department of Anesthesiology, Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT 06510

Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN--related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN- and IFN--inducible chemokines, defining an IFN- axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN- axis, but not that of IL-18. Activation of the IFN- axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN- and IFN--inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN- in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN- secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grant PO1 HL70295.

² H.R. and S.I.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. George Tellides, 295 Congress Avenue, Boyer Center for Molecular Medicine 454, New Haven, CT 06510. E-mail address: george.tellides{at}yale.edu

⁴ Abbreviations used in this paper: CRP, C-reactive protein; oxLDL, oxidized low-density lipoprotein; CABG, coronary artery bypass graft; CsA, cyclosporin A; PI, propidium iodide; CPB, cardiopulmonary bypass; CAD, coronary artery disease.

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