The p38 mitogen-activated protein kinase cascade modulates T helper type 17 differentiation and functionality in multiple sclerosis

Claudio Sette, Diletta Di Mitri, Manolo Sambucci, Maria Loiarro, Marco De Bardi, Elisabetta Volpe, Maria Teresa Cencioni, Claudio Gasperini, Diego Centonze, Arne N. Akbar, Giovanna Borsellino, Luca Battistini

Research output: Contribution to journalArticle

16 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)251-263
Number of pages13
Publication statusPublished - 2015


  • Adenosine Triphosphatases
  • Adult
  • Autoimmunity
  • Case-Control Studies
  • Cation Transport Proteins
  • Cell Differentiation
  • Cells, Cultured
  • Copper-transporting ATPases
  • Enzyme Activation
  • Eukaryotic Initiation Factor-4E
  • Experimental autoimmune encephalomyelitis/multiple sclerosis
  • Female
  • Humans
  • Immunology
  • Immunology and Allergy
  • Interleukin-17
  • Interleukins
  • Lymphocyte Activation
  • MAP Kinase Signaling System
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting
  • Neuroimmunology
  • Phenotype
  • Phosphorylation
  • Signal transduction
  • T cells
  • Th17 Cells
  • p38 Mitogen-Activated Protein Kinases


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