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Halofuginone-induced amino acid starvation regulates Stat3-dependent Th17 effector function and reduces established autoimmune inflammation.
Carlson, Thaddeus J; Pellerin, Alex; Djuretic, Ivana M; Trivigno, Catherine; Koralov, Sergei B; Rao, Anjana; Sundrud, Mark S.
Afiliação
  • Carlson TJ; Tempero Pharmaceuticals, Inc., Cambridge, MA 02139;
J Immunol ; 192(5): 2167-76, 2014 Mar 01.
Article em En | MEDLINE | ID: mdl-24489094
The IL-23 pathway is genetically linked to autoimmune disease in humans and is required for pathogenic Th17 cell function in mice. However, because IL-23R-expressing mature Th17 cells are rare and poorly defined in mice at steady-state, little is known about IL-23 signaling. In this study, we show that the endogenous CCR6(+) memory T cell compartment present in peripheral lymphoid organs of unmanipulated mice expresses Il23r ex vivo, displays marked proinflammatory responses to IL-23 stimulation in vitro, and is capable of transferring experimental autoimmune encephalomyelitis. The prolyl-tRNA synthetase inhibitor halofuginone blocks IL-23-induced Stat3 phosphorylation and IL-23-dependent proinflammatory cytokine expression in endogenous CCR6(+) Th17 cells via activation of the amino acid starvation response (AAR) pathway. In vivo, halofuginone shows therapeutic efficacy in experimental autoimmune encephalomyelitis, reducing both established disease progression and local Th17 cell effector function within the CNS. Mechanistically, AAR activation impairs Stat3 responses downstream of multiple cytokine receptors via selective, posttranscriptional suppression of Stat3 protein levels. Thus, our study reveals latent pathogenic functions of endogenous Th17 cells that are regulated by both IL-23 and AAR pathways and identifies a novel regulatory pathway targeting Stat3 that may underlie selective immune regulation by the AAR.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação Linfocitária / Encefalomielite Autoimune Experimental / Fator de Transcrição STAT3 / Células Th17 / Aminoácidos Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação Linfocitária / Encefalomielite Autoimune Experimental / Fator de Transcrição STAT3 / Células Th17 / Aminoácidos Idioma: En Ano de publicação: 2014 Tipo de documento: Article