Cytokines (interferon- γ and tumor necrosis factor– α )-induced nuclear factor– κ B activation and chemokine (C-X-C motif) ligand 10 release in Graves disease and ophthalmopathy are modulated by pioglitazone

Abstract Until now, the following are not known: (1) the mechanisms underlying the induction of chemokine (C-X-C motif) ligand 10 (CXCL10) secretion by cytokines in thyrocytes; (2) if pioglitazone is able, like rosiglitazone, to inhibit the interferon (IFN)- γ –induced chemokine expression in Graves disease (GD) or ophthalmopathy (GO); and (3) the mechanisms underlying the inhibition by thiazolidinediones of the cytokines-induced CXCL10 release in thyrocytes. The aims of this study were (1) to study the mechanisms underlying the induction of CXCL10 secretion by cytokines in GD thyrocytes; (2) to test the effect of pioglitazone on IFN γ -inducible CXCL10 secretion in primary thyrocytes, orbital fibroblasts, and preadipocytes from GD and GO patients; and (3) to evaluate the mechanism of action of thiazolidinediones on nuclear factor (NF)– κ B activation. The results of the study (1) demonstrate that IFN γ + TNF α enhanced the DNA binding activity of NF- κ B in GD thyrocytes, in association with the release of CXCL10; (2) show that pioglitazone exerts a dose-dependent inhibition on IFN γ + TNF α –induced CXCL10 secretion in thyrocytes, orbital fibroblasts, and preadipocytes, similar to the effect observed with rosiglitazone; and (3) demonstrate that thiazolidinediones (pioglitazone and rosiglitazone) act by reducing the IFN γ + TNF α activation of NF- κ B in Graves thyrocytes. To the best of our knowledge, this is the first study showing that cytokines are able to activate NF- κ B in Graves thyrocytes and a parallel inhibitory effect of pioglitazone both on CXCL10 chemokine secretion and NF- κ B activation. Future studies will be needed to verify if new targeted peroxisome proliferator-activated receptor– γ activators may be able to exert the anti-inflammatory effects without the risk of expanding retrobulbar fat mass.