Faculty Bibliography

Sjögren syndrome is a chronic autoimmune disease that typically affects the salivary and lacrimal glands. Aside from the common glandular signs and symptoms, Sjögren syndrome may also cause mononuclear infiltration and immune complex deposition involving extraglandular sites producing several extraglandular manifestations (EGM). The prevalence of EGMs varies greatly depending on the particular manifestation. This article examines the ways that EGMs may present in patients with primary Sjögren syndrome. The focus is on the more prevalent and significant EGMs including involvement of the nervous system, pulmonary manifestations, vasculitis associated with primary Sjögren syndrome, and arthropathy.

Tumor necrosis factor- (TNF-) alpha is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-alpha monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-alpha and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) alpha, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-alpha alone or TNF-alpha with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-alpha significantly reduced both ABCA1 and LXR-alpha mRNA (to 68.5 +/- 1.59%, P < 0.05, and 41.2 +/- 0.25%, P < 0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-alpha effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-alpha. TNF-alpha treatment significantly reduces ABCA1 and LXR-alpha expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes.

Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Known cardioprotective and anti-inflammatory properties of resveratrol have spurred investigation of the mechanisms involved. The present study explored potential atheroprotective actions of resveratrol on cholesterol metabolism in cells of the arterial wall, including human macrophages and arterial endothelium. Using QRT-PCR and Western blotting techniques, we measured expression of the proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and SR-B1) and the scavenger receptors responsible for uptake of modified cholesterol (CD36, SR-A1 and LOX-1). We analyzed the effect of resveratrol on apoA-1-and HDL-mediated cholesterol efflux in human THP-1 macrophages. The effect of resveratrol on oxLDL internalization and foam cell formation were evaluated using confocal and light microscopy. Our data indicate that resveratrol regulates expression of major proteins involved in cholesterol transport, promotes apoA-1 and HDL-mediated efflux, downregulates oxLDL uptake and diminishes foam cell formation. Mechanistically, resveratrol effects were dependent upon PPAR-gamma and adenosine 2A receptor pathways. For the first time we demonstrate that resveratrol regulates expression of the cholesterol metabolizing enzyme cytochrome P450 27-hydroxylase, providing efficient cholesterol elimination via formation of oxysterols. This study establishes that resveratrol attenuates lipid accumulation in cultured human macrophages via effects on cholesterol transport. Further in vivo studies are needed to determine whether resveratrol may be an additional resource available to reduce lipid deposition and atherosclerosis in humans.