Abstract
Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP(139-151)-induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP(139-151)-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4 T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27) in autoreactive CD4 T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / metabolism
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Antigens, Differentiation / metabolism
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Cytokines / immunology
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Disease Progression
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / physiopathology
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Female
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Humans
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Hypersensitivity, Delayed
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Integrin alpha4beta1 / immunology
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Leptin / immunology
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Leptin / physiology*
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Mice
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Myelin Proteolipid Protein / immunology
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Peptide Fragments / immunology
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, Leptin
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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T-Lymphocytes / immunology*
Substances
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Antibodies
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Antigens, Differentiation
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Cytokines
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Integrin alpha4beta1
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LEPR protein, human
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Leptin
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Myelin Proteolipid Protein
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OX40Ig
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Peptide Fragments
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Receptors, Cell Surface
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Receptors, Leptin
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Recombinant Fusion Proteins
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leptin receptor, mouse
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myelin proteolipid protein (139-151)
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Intercellular Adhesion Molecule-1