Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes

Abstract

CXC chemokine ligand 10 (CXCL10) plays a pivotal role in the self-perpetuation of the inflammatory processes in patients with autoimmune thyroid disease. Treatment with methimazole (MMI) reduces serum CXCL10 in patients with Graves' disease. In isolated human thyrocytes, tumor necrosis factor (TNF)α demonstrates a potent synergistic effect on interferon (IFN)γ-induced CXCL10 secretion. We investigated the mechanism underlying the synergism between IFNγ and TNFα and the elfect of MMI on CXCL10 secretion in human thyrocytes. A peroxisome proliferator-activated receptor γ agonist, rosiglitazone (RGZ), a known inhibitor of T helper 1 (Th1)-mediated responses, was also studied for comparison. Experiments were carried out in human thyrocytes isolated from internodular parenchyma of thyroid tissues derived from patients who had undergone surgery for multinodular goiter. ELISA was used to measure CXCL10 levels in culture supernatant. Flow cytometry was used to assess IFNγ membrane receptor expression. Specific mRNA analysis was performed by Taqman real-time PCR. Immunofluorescence was performed to detect nuclear translocation of nuclear factor-κB (NF-κB). In human thyrocytes, the synergistic effect of TNFα with IFNγ on CXCL10 secretion is due to the upregulation of IFNγ receptor expression. MMI decreased cytokine-induced CXCL10 secretion by reducing TNFα-induced upregulation of the IFNγ receptor. RGZ decreased the cytokine-induced CXCL10 secretion by impairing NF-κB translocation, without affecting IFNγ receptor. MMI and RGZ targeted thyrocytes with the same pharmacological potency, likely acting throughout different mechanisms. Targeting T helper 1-mediated autoimmune thyroid disease with drugs that impair different intracellular pathways could be a novel pharmacological tool. © 2007 Society for Endocrinology.