CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
REGULATION OF THE NUCLEAR FACTOR NF-κB SIGNALING PATHWAY IN RESPONSE TO THYROIDSTIMULATING HORMONE RECEPTOR ACTIVATION
Autor/es:
REALE, C; VITO, P; NAZAR, M; PEYRET, V; NICOLA, JP; MARTIN, M; MASINI-REPISO, AM
Lugar:
Rio de Janeiro
Reunión:
Congreso; XVI Congreso de la Sociedad Latinoamericana de Tiroides; 2017
Institución organizadora:
Sociedad Latinoamericana de Tiroides
Resumen:
Introduction: Although activation of NF-κB signaling in thyroid follicular cells downstream to TSH receptor engagementhas been reported, the downstream signaling that result in NF-κB activation remain unexplored. Previously, we demonstratedthe participation of NF-κB in the upregulation of different genes involved in thyroid hormonogenesis in response to bacteriallipopolysaccharide. Recent data demonstrated that genetic deletion of NEMO in the thyroid tissue lead to apoptotic death ofthyroid follicular cells. Objective: We sought to elucidate the mechanism that mediates NF-κB signaling activation in responseto the activation of the TSH receptor. Results and Discussion: TSH treatment leads to PKC-mediated phosphorylation of theIKK regulatory complex, degradation of the cytosolic IκB-α inhibitor, and nuclear translocation of the NF-κB p65 subunit,thus indicating activation of the canonical NF-κB signaling. Moreover, TSH stimulation phosphorylates the kinase TAK-1 andits knock-down abolished TSH-induced IKK complex phosphorylation and the transcriptional activity of NF-κB. AlthoughPKA inhibition did not modulate TSH-induced nuclear recruitment of p65, TSH induces the transcriptional activity of theNF-κB subunit p65 in a PKA-dependent phosphorylation on Ser-276. Additionally, p65 phosphorylation on Ser-276 inducedacetyl transferases CBP/p300 recruitment leading to its acetylation on Lys-310, thus enhancing its transcriptional activity.Evaluation of the role played by NF-κB in thyroid physiology demonstrated that the NF-κB inhibitor BAY 11-7082 reducedTSH-induced expression of the proteins involved in thyroid hormonogenesis Of note, the role of NF-κB in thyroid physiologywas confirmed assessing TSH-induced gene expression in primary cultures of NEMO-deficient thyrocytes. Moreover, chromatinimmunoprecipitation and knock-down experiments revealed that p65 is a transcriptional effector of TSH actions inducingthe expression of genes involved in thyroid hormonogenesis. Altogether our results point to NF-κB as a pivotal mediator in theTSH-induced thyroid follicular cell differentiation. Increasing evidence indicates that NF-κB participates in the pathogenesisof autoimmune diseases, being a key factor in the interface between inflammation and cancer. We speculate that a misbalancein TSH signaling regulation could have potential implication in thyroid pathophysiology through the modulation of NF-κBsignaling.