Hypercholesterolemia leads to elevated TGF-beta1 activity and T helper 3-dependent autoimmune responses in atherosclerotic mice.
OBJECTIVE
The pathogenesis of atherosclerosis involves inflammation and immune reactions. Low-density lipoproteins accumulate and are oxidized (oxLDL) in the arterial intima during hypercholesterolemia, leading to activation of endothelial cells, macrophages and T cells. We have previously found that severe hypercholesterolemia can induce a switch of autoimmune responses from T helper (Th)1 to Th2 effector type in atherosclerotic apoE knockout (E0) mice. The present study was performed to investigate whether Th3 immune effector responses and their inducing cytokine, transforming growth factor-beta (TGF-beta) are affected by hypercholesterolemia.


RESULTS
In E0 mice fed with high cholesterol diet and in C57BL/6J mice treated with poloxamer P-407, an agent that elevates plasma cholesterol and triglycerides, severe hypercholesterolemia led to elevated circulating TGF-beta1 levels, increased TGF-beta1(+)CD4(+) Th3 cells in lesions and spleen, and increased Th3 dependent IgG2b antibodies to oxLDL. A positive correlation was observed between plasma TGF-beta1 and cholesterol levels and between plasma TGF-beta1 and IgG2b anti-oxLDL.


CONCLUSIONS
Such elevation of TGF-beta may increase the stability of plaques by inhibiting T cell responses and macrophage activation and by stimulating collagen synthesis. This new finding could be important in the regulation of immune activity, inflammation and fibrosis in the atherosclerotic plaque.
Zhou
Xinghua
X
Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden. Xinghua.Zhou@ki.se
Johnston
Thomas P
TP
Johansson
Daniel
D
Parini
Paolo
P
Funa
Keiko
K
Svensson
Jan
J
Hansson
Göran K
GK
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D002791:Cholesterol, Dietary / Q000097:blood; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000097:blood / Q000209:etiology / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D008077:Lipoproteins, LDL / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020442:Poloxamer; D012720:Severity of Illness Index; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000097:blood*; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
D001057:Apolipoproteins E; D001323:Autoantibodies; D002791:Cholesterol, Dietary; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D020442:Poloxamer; D003094:Collagen