title: Astrocyte-specific IKK2 activation in mice is sufficient to induce neuroinflammation but does not increase susceptibility to MPTP.
abstract: A key regulator of inflammatory gene expression is the transcription factor NF-κB that is controlled by the IκB proteins. We used a transgenic mouse model expressing a constitutively active IκB-kinase-2 (IKK2-CA) in astrocytes under control of the human glial fibrillary acidic protein promotor (IKK2-mice) to investigate neuroinflammation, proinflammatory cytokine expression, microglial activation and a potential enhanced susceptibility to the neurotoxin MPTP (4×10 mg/kg). Readouts included the determination of cytokines, striatal dopamine (DA), nigral tyrosine hydroxylase (TH) positive neurons, microglial activation and motor activity. IKK2-CA expression in astrocytes conditionally induced by the tet-off system resulted in a widespread neuroinflammation indicated by the increased expression of inflammatory cytokines and the presence of activated microglia and astrogliosis. Additionally, striatal DA concentrations but not nigral TH-positive neurons were reduced in IKK2-mice by 20%. Motor activity of IKK2-mice was not affected. Surprisingly, there was a similar reduction in striatal DA concentrations and the number of nigral TH-positive neurons in IKK2 and control mice after MPTP treatment. In conclusion, although naïve IKK2-mice showed reduced striatal DA concentrations and an increase in inflammatory markers in the brain, a higher susceptibility to MPTP was not observed. This finding argues against a prominent role of astrocyte specific, IKK2-mediated neuroinflammation in MPTP-induced neurodegeneration.
authors: CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
authors: Patrick
authors: P
authors: Oeckl
authors: Michael
authors: M
authors: Lattke
authors: Thomas
authors: T
authors: Wirth
authors: Bernd
authors: B
authors: Baumann
authors: Boris
authors: B
authors: Ferger
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004789:Enzyme Activation / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology*; D020267:MPTP Poisoning / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051550:I-kappa B Kinase