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1.
EMBO J ; 38(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770344

RESUMO

T helper 17 (Th17)-cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17-cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical "AGG" elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il17a/Il17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.


Assuntos
Colite/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/prevenção & controle , Mucosa Intestinal/efeitos dos fármacos , Fator Inibidor de Leucemia/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT4/fisiologia , Animais , Células Cultivadas , Colite/induzido quimicamente , Colite/imunologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Interleucina-17/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fator de Transcrição STAT3/genética , Transdução de Sinais , Células Th17/imunologia
2.
Sci Rep ; 6: 39517, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28004755

RESUMO

Cytoplasmic STAT3, after activation by growth factors, translocates to different subcellular compartments, including nuclei and mitochondria, where it carries out different biological functions. However, the precise mechanism by which STAT3 undergoes mitochondrial translocation and subsequently regulates the tricarboxylic acid (TCA) cycle-electron transport chain (ETC) remains poorly understood. Here, we clarify this process by visualizing STAT3 acetylation in starved cells after serum reintroduction or insulin stimulation. CBP-acetylated STAT3 undergoes mitochondrial translocation in response to serum introduction or insulin stimulation. In mitochondria, STAT3 associates with the pyruvate dehydrogenase complex E1 (PDC-E1) and subsequently accelerates the conversion of pyruvate to acetyl-CoA, elevates the mitochondrial membrane potential, and promotes ATP synthesis. SIRT5 deacetylates STAT3, thereby inhibiting its function in mitochondrial pyruvate metabolism. In the A549 lung cancer cell line, constitutively acetylated STAT3 localizes to mitochondria, where it maintains the mitochondrial membrane potential and ATP synthesis in an active state.


Assuntos
Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Transporte Proteico , Piruvatos/metabolismo , Fator de Transcrição STAT3/metabolismo , Células A549 , Acetilcoenzima A/metabolismo , Acetilação , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Ciclo do Ácido Cítrico , Citoplasma/metabolismo , Fibroblastos/metabolismo , Células HEK293 , Células HeLa , Humanos , Insulina/metabolismo , Camundongos , Oxirredução , Processamento de Proteína Pós-Traducional , Complexo Piruvato Desidrogenase/metabolismo , Ácido Pirúvico/metabolismo
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