Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro.

Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 microM) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 microg ml(-1)) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR gamma). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF kappa B) expression and reduced uptake of(125)I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR gamma levels and abolished NF kappa B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- alpha). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR gamma and NF kappa B in the modulation of the inflammatory processes by statins. Copyright 2002 Elsevier Science Ltd.