Abstract
The efficiency of activating latent transforming growth factor (TGF)-β1 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-β1 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-β1 was determined for 32 patients with SLE and 33 age-matched and sex-matched control individuals by quantifying the increase in active TGF-β1 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-β1 AI for SLE patients were within the normal range. There was a significant inverse association between TGF-β1 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-β1 AI and low-density lipoprotein cholesterol (r = -0.404; P = 0.022) and between TGF-β1 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 ≥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-β1 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.
Highlights
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
Correlation of low-density lipoprotein (LDL) cholesterol and carotid intima-media thickness (IMT) score with TGFβ1 Activation Index. (a)Correlation of LDL cholesterol and transforming growth factor (TGF)-β1 Activation Index, using Pearson test. (b) Carotid artery IMT scores were correlated with TGF-β1 Activation Index for control patients and systemic lupus erythematosus (SLE) patients, using Pearson correlation
We investigated the ability of SLE patients and control individuals to activate latent TGF-β1 in an in vitro assay that utilizes the physiological activation of latent TGF-β1 that occurs normally during blood clotting
Summary
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. 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]
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