Atorvastatin Attenuates TNF-alpha Production via Heme Oxygenase-1 Pathway in LPS-stimulated RAW264.7 Macrophages

Biomed Environ Sci. 2014 Oct;27(10):786-93. doi: 10.3967/bes2014.114.

Abstract

Objective: To assess the effect of atorvastatin on lipopolysaccharide (LPS)-induced TNF-α production in RAW264.7 macrophages.

Methods: RAW264.7 macrophages were treated in different LPS concentrations or at different time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-α mRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HO activity was assayed.

Results: LPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1 activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate in regulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin on TNF-α expression and production in LPS-stimulated macrophages.

Conclusion: Atorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways, suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.

Keywords: Atorvastatin; Heme oxygenase-1; Lipopolysaccharide; Tumor necrosis factor-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Atorvastatin
  • Enzyme Activation / drug effects
  • Heme Oxygenase-1 / genetics*
  • Heme Oxygenase-1 / metabolism
  • Heptanoic Acids / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Pyrroles / pharmacology*
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Adjuvants, Immunologic
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipopolysaccharides
  • Membrane Proteins
  • Pyrroles
  • Tumor Necrosis Factor-alpha
  • Atorvastatin
  • Heme Oxygenase-1
  • Hmox1 protein, mouse