title: Berberine inhibits HIV protease inhibitor-induced inflammatory response by modulating ER stress signaling pathways in murine macrophages.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Microbiology & Immunology and Internal Medicine/Gastroenterology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zha
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Studer
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D000069446:Atazanavir Sulfate; D001599:Berberine / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D061466:Lopinavir; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000633:toxicity; D011725:Pyridines / Q000633:toxicity; D011744:Pyrimidinones / Q000633:toxicity; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D017320:HIV Protease Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D001599:Berberine; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D048049:Extracellular Signal-Regulated MAP Kinases; D019438:Ritonavir