Cytokines (interferon-γ and tumor necrosis factor-α)-induced nuclear factor-κB 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 IFNγ-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)-κB activation. The results of the study (1) demonstrate that IFNγ + TNFα enhanced the DNA binding activity of NF-κB in GD thyrocytes, in association with the release of CXCL10; (2) show that pioglitazone exerts a dose-dependent inhibition on IFNγ + TNFα-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 IFNγ + TNFα activation of NF-κB in Graves thyrocytes. To the best of our knowledge, this is the first study showing that cytokines are able to activate NF-κB in Graves thyrocytes and a parallel inhibitory effect of pioglitazone both on CXCL10 chemokine secretion and NF-κB 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.

• Authors: Alessandro Antonelli, Silvia Martina Ferrari, Poupak Fallahi, Simona Piaggi, Aldo Paolicchi, Stefano Sellari Franceschini, Mario Salvi, Ele Ferrannini
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 60 Issue 2 Pg. 277-83 (Feb 2011) ISSN: 1532-8600 [Electronic] United States
• PMID: 20206950 (Publication Type: Journal Article)
• Copyright: © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• CXCL10 protein, human
• Chemokine CXCL10
• NF-kappa B
• PPAR gamma
• Thiazolidinediones
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Pioglitazone

Topics

• Adipocytes (drug effects, metabolism)
• Adult
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cells, Cultured
• Chemokine CXCL10 (antagonists & inhibitors, metabolism)
• Female
• Fibroblasts (drug effects, metabolism)
• Graves Disease (metabolism)
• Graves Ophthalmopathy (metabolism)
• Humans
• Interferon-gamma (metabolism)
• Male
• Middle Aged
• NF-kappa B (metabolism)
• PPAR gamma (agonists)
• Pioglitazone
• Thiazolidinediones (pharmacology)
• Thyroid Gland (drug effects, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)