Regulation of the Nuclear Factor NF-kB Signaling Pathway in Response to Thyroid Stimulating Hormone Receptor Activation

NICOLA JP; NAZAR M; REALE C; MARTÍN M; PEYRET V; VITO P; MASINI - REPISO AM

Rio de Janeiro

Congreso; XVI Latin American Thyroid Congress (LATS); 2017

Latin American Thyroid Society (LATS).

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 demonstrated the participation of NF-κB in the upregulation of different genes involved in thyroid hormonogenesisin response to bacterial lipopolysaccharide. Recent data demonstrated that genetic deletion of NEMOin the thyroid tissue lead to apoptotic death of thyroid follicular cells.Objective: We sought toelucidate the mechanismthat mediates NF-κB signaling activation in response to the activation of the TSH receptor.Results and discussion:TSH treatment leads to PKC-mediated phosphorylation of the IKK 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 and its knock-down abolished TSH-induced IKK complex phosphorylation and the transcriptional activity of NF-κB.Although PKA inhibition did not modulate TSH-induced nuclear recruitment of p65, TSH induces the transcriptional activity of the NF-κBsubunit p65 in a PKA-dependent phosphorylation on Ser-276. Additionally, p65 phosphorylation on Ser-276 induced acetyl transferases CBP/p300recruitmentleading 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 BAY11-7082 reduced TSH-induced expression of the proteins involved in thyroid hormonogenesisOf note, the role of NF-κB in thyroid physiology was confirmed assessing TSH-induced gene expression in primary cultures of NEMO-deficient thyrocytes. Moreover, chromatin immunoprecipitation and knock-down experiments revealed that p65 is a transcriptional effector of TSH actions inducing the expression of genes involved in thyroid hormonogenesis. Altogether our results point to NF-κB as a pivotal mediator in the TSH-induced thyroid follicular cell differentiation.Increasing evidence indicates that NF-κB participates in the pathogenesis of autoimmune diseases, being a key factor in the interface between inflammation and cancer. We speculate that a misbalance in TSH signaling regulationcould have potential implication in thyroid pathophysiology through the modulation of NF-κB signaling.