Activation of transforming growth factor-β1 and early atherosclerosis in systemic lupus erythematosus

Transforming growth factor (TGF)-β1 is the most potent naturally occurring immunosuppressant [1]; it is produced by all cells of the immune system and plays a fundamental role in controlling proliferation and the fate of cells through apoptosis. In TGF-β1 knockout mice [2] lack of TGF-β1 initiates indiscriminate loss of self-tolerant T cells. Consequential dysregulation of B cell activity leads to production of systemic lupus erythematosus (SLE)-like autoantibodies [3] and development of a lupus-like illness, resulting in early death at 3–4 weeks [2]. Preliminary human studies suggest that TGF-β1 expression in SLE may be dysregulated. Production of TGF-β1 by lymphocytes isolated from SLE patients is reduced compared with that in control individuals [4]. Spontaneous polyclonal IgG and autoantibody production can be abrogated by treatment with interleukin-2 and TGF-β1 [5].Atherosclerosis is a major cause of mortality and morbidity in SLE, with 6–10% of patients developing premature clinical coronary heart disease [6]. The 'protective cytokine hypothesis', recently reviewed [7], proposes that active TGF-β1 in the vascular wall is required to maintain the normal vascular wall structure and controls the balance between inflammation and extracellular matrix deposition in atherosclerosis. TGF-β1 is an inhibitor of smooth muscle and endothelial cell proliferation [8]. Mice heterozygous for the deletion of the TGF-β1 gene (tgfβ1+/-) have a 50% reduction in levels of TGF-β1 in artery walls and, when fed a cholesterol-enriched diet, such mice exhibit marked deposition of lipid in the artery wall as compared with wild-type mice [9]. In experimental models the evidence suggests that lack of TGF-β1 signalling promotes the development of atherosclerotic lesions and unstable plaques [10]. Therefore, because impairment in the TGF-β1 pathway has been associated with both an SLE-like illness and enhanced atherogenesis, we hypothesize that this pathway might represent a link between th