Circulation Research. 2002;90:1064-1071
Published online before print April 18, 2002, doi: 10.1161/01.RES.0000018941.10726.FA
Published online before print April 18, 2002, doi: 10.1161/01.RES.0000018941.10726.FA
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© 2002 American Heart Association, Inc.
Molecular Medicine |
Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor–Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes
From the Departments of Medicine (L.J.P, G.S., J.A.B.), Experimental Pathology (L.J.P., M.C.F., J.A.B.), Surgery (M.P.F.), and Microbiology and Immunology (M.P.F.), University Of California Los Angeles; Department of Immunology (N.K., L.K.C., W.A.B.), The Scripps Research Institute, La Jolla; and the Division of Developmental Immunology (H.C.), The La Jolla Institute For Allergy and Immunology, San Diego, Calif.
Correspondence to Laura J. Pinderski, University of Alabama, Birmingham, Division of Cardiology, THT 332, 1900 University Blvd, Birmingham, AL 35294-0006. E-mail lpinderski{at}cardio.com.uab.edu
Previous studies demonstrated that interleukin-10 (IL-10) overexpression decreases formation of early fatty-streak lesions in mice independent of lipoprotein levels. The present studies, using bone marrow transplantation, demonstrate that overexpression of IL-10 by T cells inhibits advanced atherosclerotic lesions in LDL receptor–null mice fed an atherogenic diet. In mice receiving bone marrow from the IL-10 transgenic mice compared with those receiving wild-type marrow, there was a 47% decrease in lesion size and a marked decrease in lesion complexity with an 80% reduction in the necrotic core. Accumulation of cholesterol and phospholipid oxidation products in the aorta was decreased by 50% to 80%, unrelated to plasma lipid or IL-10 levels. Our studies also provide insight into the mechanism of the IL-10–mediated decrease in lesion size. Although a strong influence toward a Th1 phenotype has previously been demonstrated in atherosclerotic models, T lymphocytes in the IL-10 transgenic (Tg) group revealed a marked shift to a Th2 phenotype, with decreased IFN-
production and an increase in IL-10. Evaluation of specific immunoglobulin subclasses demonstrated a preponderance of IgG1 isotype, characteristic of a Th2 influence on B cell immunoglobulin class-switching in the IL-10 Tg group. A major finding of these studies was altered monocyte/macrophage function in the IL-10 Tg group. Monocytes showed a decrease in activation resulting in decreased expression of IFN-. Furthermore, macrophage foam cells within lesions of the IL-10 Tg group exhibited markedly decreased apoptosis. These studies demonstrate that T lymphocyte IL-10 can influence the function of other immune cells to reduce the development of advanced atherosclerotic lesions in mice.
Key Words: cytokine • LDL receptor • B lymphocytes • antibodies • apoptosis
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