Berberine Inhibits HIV Protease Inhibitor-Induced Inflammatory Response by Modulating ER Stress Signaling Pathways in Murine Macrophages

PLoS One. 2010 Feb 9;5(2):e9069. doi: 10.1371/journal.pone.0009069.

Abstract

Background: HIV protease inhibitor (PI)-induced inflammatory response plays an important role in HIV PI-associated dyslipidemia and cardiovascular complications. This study examined the effect of berberine, a traditional herb medicine, on HIV PI-induced inflammatory response and further investigated the underlying cellular/molecular mechanisms in macrophages.

Methodology and principal findings: Cultured mouse J774A.1 macrophages and primary mouse macrophages were used in this study. The expression of TNF-alpha and IL-6 were detected by real-time RT-PCR and ELISA. Activations of ER stress and ERK signaling pathways were determined by Western blot analysis. Immunofluorescent staining was used to determine the intracellular localization of RNA binding protein HuR. RNA-pull down assay was used to determine the association of HuR with endogenous TNF-alpha and IL-6. Berberine significantly inhibited HIV PI-induced TNF-alpha and IL-6 expression by modulating ER stress signaling pathways and subsequent ERK activation, in turn preventing the accumulation of the RNA binding protein HuR in cytosol and inhibiting the binding of HuR to the 3'-UTRs of TNF-alpha and IL-6 in macrophages.

Conclusions and significance: Inhibition of ER stress represents a key mechanism by which berberine prevents HIV PI-induced inflammatory response. Our findings provide a new insight into the molecular mechanisms of berberine and show the potential application of berberine as a complimentary therapeutic agent for HIV infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism
  • Atazanavir Sulfate
  • Berberine / pharmacology*
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Endoplasmic Reticulum / metabolism*
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HIV Protease Inhibitors / toxicity*
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Lopinavir
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Oligopeptides / toxicity
  • Pyridines / toxicity
  • Pyrimidinones / toxicity
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ritonavir / toxicity
  • Signal Transduction / drug effects*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, Surface
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • HIV Protease Inhibitors
  • Inflammation Mediators
  • Interleukin-6
  • Oligopeptides
  • Pyridines
  • Pyrimidinones
  • RNA-Binding Proteins
  • Tumor Necrosis Factor-alpha
  • Berberine
  • Lopinavir
  • Atazanavir Sulfate
  • Extracellular Signal-Regulated MAP Kinases
  • Ritonavir