Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells

Autor(es):Mostrar menos -

Freitas, Beatriz C. G. ^[1] ; Gereben, Balazs ^[2] ; Castillo, Melany ^[3] ; Kallo, Imre ^[2] ; Zeoeld, Aniko ^[2] ; Egri, Peter ^[2] ; Liposits, Zsolt ^[2] ; Zavacki, Ann Marie ^[4] ; Maciel, Rui M. B. ^[1] ; Jo, Sungro ^[3] ; Singru, Praful ^[5] ; Sanchez, Edith ^[5] ; Lechan, Ronald M. ^{[5, 6]} ; Bianco, Antonio C. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Mol Endocrinol Lab, Div Endocrinol, Dept Med, Sao Paulo - Brazil

^[2] Hungarian Acad Sci, Inst Expt Med, Lab Endocrine Neurobiol, Budapest - Hungary

^[3] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 - USA

^[4] Brigham & Womens Hosp, Thyroid Sect, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 - USA

^[5] Tufts Med Ctr, Div Endocrinol Diabet & Metab, Dept Med, Tupper Res Inst, Boston, MA - USA

^[6] Tufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 - USA

• Tipo de documento: Artigo Científico
• Fonte: Journal of Clinical Investigation; v. 120, n. 6, p. 2206-2217, JUN 2010.
• Citações Web of Science: 95

Resumo

Hypothyroidism in humans is characterized by severe neurological consequences that are often irreversible, highlighting the critical role of thyroid hormone (TH) in the brain. Despite this, not much is known about the signaling pathways that control TH action in the brain. What is known is that the prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by type 2 deiodinase (D2) and that this occurs in astrocytes, while TH receptors and type 3 deiodinase (D3), which inactivates T3, are found in adjacent neurons. Here, we modeled TH action in the brain using an in vitro coculture system of D2-expressing H4 human glioma cells and D3-expressing SK-N-AS human neuroblastoma cells. We found that glial cell D2 activity resulted in increased T3 production, which acted in a paracrine fashion to induce T3-responsive genes, including ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), in the cocultured neurons. D3 activity in the neurons modulated these effects. Furthermore, this paracrine pathway was regulated by signals such as hypoxia, hedgehog signaling, and LPS-induced inflammation, as evidenced both in the in vitro coculture system and in in vivo rat models of brain ischemia and mouse models of inflammation. This study therefore presents what we believe to be the first direct evidence for a paracrine loop linking glial D2 activity to TH receptors in neurons, thereby identifying deiodinases as potential control points for the regulation of TH signaling in the brain during health and disease. (AU)

• Processo FAPESP: 05/55826-4 - Estudo das vias das desiodases na glia e nos neurônios modulando a ação do hormônio tiroideano no cérebro
• Beneficiário: Beatriz Camille Grigalis de Freitas
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 05/55825-8 - Selenodesiodases de iodotironinas: estudos moleculares e biológicos envolvendo localização de polimorfismos de um único nucleotídeo (SNPs) nos genes relacionados às desiodases e estudo funcional dos domínios da VDU-1 e WSB-1
• Beneficiário: Rui Monteiro de Barros Maciel
• Modalidade de apoio: Auxílio à Pesquisa - Regular