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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., Methods and 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.