title: Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression.
abstract: BACKGROUND
  It is well known that most neurodegenerative diseases are associated with microglia-mediated inflammation. Our previous research demonstrates that the CD40 signaling is critically involved in microglia-related immune responses in the brain. For example, it is well known that the activation of the signal transducer and activator of transcription (STAT) signaling pathway plays a central role in interferon-gamma (IFN-gamma)-induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN-gamma and amyloid-beta (A beta) peptide. Recent studies have shown that certain flavonoids possess anti-inflammatory and neuroprotective properties distinct from their well-known anti-oxidant effects. In particular, flavonoids, apigenin and luteolin have been found to be effective CD40 immunomodulators.
  
  
  METHODS
  Cultured microglia, both N9 and primary derived lines, were treated with flavonoids in the presence of IFN-gamma and/or CD40 ligation to assess any anti-inflammatory effects and/or mechanisms. CD40 expression on microglia was analyzed by fluorescence activated cell sorting (FACS). Anti-inflammatory effects and mechanisms were confirmed by ELISA for interleukin-6 (IL-6) and TNF-alpha, lactate dehydrogenase (LDH) assay, and STAT1 Western blotting.
  
  
  RESULTS
  Apigenin and luteolin concentration-dependently suppressed IFN-gamma-induced CD40 expression. Apigenin and luteolin also suppressed microglial TNF-alpha and IL-6 production stimulated by IFN-gamma challenge in the presence of CD40 ligation. In addition, apigenin and luteolin markedly inhibited IFN-gamma-induced phosphorylation of STAT1 with little impact on cell survival.
  
  
  CONCLUSIONS
  Our findings provide further support for apigenin and luteolin's anti-inflammatory effects and suggest that these flavonoids may have neuroprotective/disease-modifying properties in various neurodegenerative disorders, including Alzheimer's disease (AD).
authors.affiliation: Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, College of Medicine, University of South Florida, Tampa, FL 33612, USA. krezaiza@health.usf.edu
authors.forename: Kavon
authors.initials: K
authors.lastname: Rezai-Zadeh
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanberg
authors.forename: Paula
authors.initials: P
authors.lastname: Bickford
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Shytle
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D019013:CD40 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D047311:Luteolin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D019013:CD40 Antigens; D007155:Immunologic Factors; D015850:Interleukin-6; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D047310:Apigenin; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D047311:Luteolin