title: The p38 mitogen-activated protein kinase cascade modulates T helper type 17 differentiation and functionality in multiple sclerosis.
abstract: The p38 mitogen-activated protein kinase cascade is required for the induction of a T helper type 17 (Th17) -mediated autoimmune response, which underlies the development and progression of several autoimmune diseases, such as experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis (MS). However, the contribution of p38 phosphorylation to human Th cell differentiation has not been clarified. Here we demonstrate that the p38 signalling pathway is implicated in the generation of Th17 lymphocytes from human CD4(+)  CD27(+)  CD45RA(+) naive T cells, both in healthy donors and in patients affected by the relapsing-remitting form of MS. Our data also indicate that p38 activation is essential for interleukin-17 release from central memory lymphocytes and committed Th17 cell clones. Furthermore, CD4(+) T cells isolated from individuals with relapsing-remitting MS display an altered responsiveness of the p38 cascade, resulting in increased p38 phosphorylation upon stimulation. These findings suggest that the p38 signalling pathway, by modulating the Th17 differentiation and response, is involved in the pathogenesis of MS, and open new perspectives for the use of p38 inhibitors in the treatment of Th17-mediated autoimmune diseases.
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.|Molecular Oncology Unit, IOR (Institute of Oncology Research), Bellinzona, Switzerland.
authors.forename: Diletta
authors.initials: D
authors.lastname: Di Mitri
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Manolo
authors.initials: M
authors.lastname: Sambucci
authors.affiliation: Neuroembryology Unit, Fondazione Santa Lucia, Rome, Italy.|Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Loiarro
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Bardi
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Volpe
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Cencioni
authors.affiliation: Lancisi Neurology Unit, San Camillo Hospital, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gasperini
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.|Department of Neurosciences, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.affiliation: Neuroembryology Unit, Fondazione Santa Lucia, Rome, Italy.|Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Borsellino
authors.affiliation: Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D000073840:Copper-Transporting ATPases; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000201:enzymology* / Q000276:immunology; D010641:Phenotype; D010766:Phosphorylation; D058504:Th17 Cells / Q000201:enzymology* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D027682:Cation Transport Proteins; D039561:Eukaryotic Initiation Factor-4E; D020381:Interleukin-17; D007378:Interleukins; D048051:p38 Mitogen-Activated Protein Kinases; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D000098546:Interleukin-21
keywords: T cells; autoimmunity; experimental autoimmune encephalomyelitis/multiple sclerosis; neuroimmunology; signal transduction