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.
Zelvyte
Inga
I
Department of Medicine, Lund University, University Hospital MAS, S-20502 Malmö, Sweden.
Dominaitiene
Ruta
R
Crisby
Milita
M
Janciauskiene
Sabina
S
D001345:Autoradiography; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018932:Chemokine CCL2; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D020782:Matrix Metalloproteinases; D017035:Pravastatin