Activation of transforming growth factor-beta1 and early atherosclerosis in systemic lupus erythematosus

The efficiency of activating latent transforming growth factor (TGF)-beta1 in systemic lupus erythematosus (SLE) may control the balance between inflammation and fibrosis, modulating the disease phenotype. To test this hypothesis we studied the ability to activate TGF-beta1 in SLE patients and control individuals within the context of inflammatory disease activity, cumulative organ damage and early atherosclerosis. An Activation Index (AI) for TGF-beta1 was determined for 32 patients with SLE and 33 age-matched and sex-matched control individuals by quantifying the increase in active TGF-beta1 under controlled standard conditions. Apoptosis in peripheral blood mononuclear cells was determined by fluorescence-activated cell sorting. Carotid artery intima-media thickness was measured using standard Doppler ultrasound. These measures were compared between patients and control individuals. In an analysis conducted in patients, we assessed the associations of these measures with SLE phenotype, including early atherosclerosis. Both intima-media thickness and TGF-beta1 AI for SLE patients were within the normal range. There was a significant inverse association between TGF-beta1 AI and levels of apoptosis in peripheral blood mononuclear cells after 24 hours in culture for both SLE patients and control individuals. Only in SLE patients was there a significant negative correlation between TGF-beta1 AI and low-density lipoprotein cholesterol (r = -0.404; P = 0.022) and between TGF-beta1 AI and carotid artery intima-media thickness (r = -0.587; P = 0.0004). A low AI was associated with irreversible damage (SLICC [Systemic Lupus International Collaborating Clinics] Damage Index > or = 1) and was inversely correlated with disease duration. Intima-media thickness was significantly linked to total cholesterol (r = 0.371; P = 0.037). To conclude, in SLE low normal TGF-beta1 activation was linked with increased lymphocyte apoptosis, irreversible organ damage, disease duration, calculated low-density lipoprotein levels and increased carotid IMT, and may contribute to the development of early atherosclerosis.