The online version of this article (doi:10.1186/1750-1326-9-56) contains supplementary material, which is available to authorized users.
Dr. Rossi received honoraria for writing from Bayer Schering and funding for traveling from Novartis, Teva, Merck Serono. She acted as an Advisory Board member of Biogen Idec, Teva and Novartis and is involved as sub-investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Schering, Sanofi-aventis, Biogen Idec, Roche.
Dr. Drulovic received funding for traveling and honoraria for speaking from Merck Serono, Teva, Novartis, Bayer Schering, Biogen Idec. She is the principal investigator in clinical trials for Merck Serono, Teva, Biogen Idec, Roche, Genzyme, Receptos.
Dr. Centonze acted as an Advisory Board member of Merck Serono, Teva, Bayer Schering, Biogen Idec, Novartis, Almirall, GW Pharmaceuticals, and received funding for traveling and honoraria for speaking or consultation fees from Merck Serono, Teva, Novartis, Bayer Schering, Sanofi-aventis, Biogen Idec, Almirall. He is the principal investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Schering, Sanofi-aventis, Biogen Idec, Roche, Almirall.
All other authors declare that they have no competing interests.
SR: study concept and design, acquisition of data, analysis, interpretation and manuscript preparation. CM, VS, GM,EV, FrB, GR, FaB, AF, RM: study concept and design, acquisition of data. SW, LB, GM, RF: study concept and design, interpretation of data. JD: study concept and design, acquisition and analysis of data. DC: study concept and design, interpretation of data and manuscript preparation. All authors read and approved the final manuscript.
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.
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.
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.
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- Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53
- BioMed Central
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