title: Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53.
abstract: BACKGROUND
  Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis (MS) and in other neurodegenerative diseases. Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients.
  
  
  RESULTS
  The effect of IL-1β, but not of TNF-α, on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-α (PFT), inhibitor of p53. The protein kinase C (PKC)/transient receptor potential vanilloid 1 (TRPV1) pathway was involved in IL-1β-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammation-relevant molecular pathway affected PFT effects on the synaptic action of IL-1β. IL-1β-induced neuronal swelling was also blocked by PFT, and IL-1β increased the expression of p21, a canonical downstream target of activated p53.Consistent with these in vitro results, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, abrogated the association between IL-1β cerebrospinal fluid (CSF) levels and disability progression in RRMS patients. The interaction between p53 and CSF IL-1β was also evaluated at the optical coherence tomography (OCT), showing that IL-1β-driven neurodegenerative damage, causing alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype.
  
  
  CONCLUSIONS
  Inflammatory synaptopathy and neurodegeneration caused by IL-1β in RRMS patients involve the apoptotic cascade. Targeting IL-1β-p53 interaction might result in significant neuroprotection in MS.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Giulia
authors.initials: G
authors.lastname: Macchiarulo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Volpe
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ruocco
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
authors.forename: Annamaria
authors.initials: A
authors.lastname: Finardi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Mancino
authors.forename: Sagit
authors.initials: S
authors.lastname: Weiss
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.forename: Jelena
authors.initials: J
authors.lastname: Drulovic
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. centonze@uniroma2.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018450:Disease Progression; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53