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.
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.
Antonelli
Alessandro
A
Department of Internal Medicine, University of Pisa-School of Medicine, I-56100 Pisa, Italy. a.antonelli@med.unipi.it
Ferrari
Silvia Martina
SM
Fallahi
Poupak
P
Piaggi
Simona
S
Paolicchi
Aldo
A
Franceschini
Stefano Sellari
SS
Salvi
Mario
M
Ferrannini
Ele
E
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006111:Graves Disease / Q000378:metabolism*; D049970:Graves Ophthalmopathy / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000077205:Pioglitazone