Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis.
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.
De Rosa
Veronica
V
Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy.
Procaccini
Claudio
C
La Cava
Antonio
A
Chieffi
Paolo
P
Nicoletti
Giovanni Francesco
GF
Fontana
Silvia
S
Zappacosta
Serafino
S
Matarese
Giuseppe
G
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed; D039041:Integrin alpha4beta1 / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D000943:Antigens, Differentiation; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039041:Integrin alpha4beta1; C515448:LEPR protein, human; D020738:Leptin; D018991:Myelin Proteolipid Protein; C406562:OX40Ig; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011993:Recombinant Fusion Proteins; C515447:leptin receptor, mouse; C435023:myelin proteolipid protein (139-151); D018799:Intercellular Adhesion Molecule-1