Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient Mice by altering lymphocyte and macrophage phenotypes.
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-gamma production and an increase in IL-10. Evaluation of specific immunoglobulin subclasses demonstrated a preponderance of IgG(1) 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-gamma. 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.
Pinderski
Laura J
LJ
Department of Medicine, University Of California Los Angeles, USA. lpinderski@cardio.com.uab.edu
Fischbein
Michael P
MP
Subbanagounder
Ganesamoorthy
G
Fishbein
Michael C
MC
Kubo
Nobuhiko
N
Cheroutre
Hilde
H
Curtiss
Linda K
LK
Berliner
Judith A
JA
Boisvert
William A
WA
D000818:Animals; D001011:Aorta / Q000737:chemistry; D001161:Arteriosclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016026:Bone Marrow Transplantation; D005434:Flow Cytometry; D007136:Immunoglobulins / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008055:Lipids / Q000032:analysis; D008074:Lipoproteins / Q000097:blood; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D007136:Immunoglobulins; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D016753:Interleukin-10