Monokine induced by interferon γ (IFNγ) (CXCL9) and IFNγ inducible T-cell α-chemoattractant (CXCL11) involvement in Graves' disease and ophthalmopathy: Modulation by peroxisome proliferator-activated receptor-γ agonists

Abstract

Context: CXC α-chemokine CXCL10/IP-10 plays an important role in the initial phases of Graves' ophthalmopathy (GO). Human thyrocytes, orbital fibroblasts, and preadipocytes are stimulated to produce CXCL10 when treated with interferon γ (IFNγ) and TNFα. Peroxisome proliferator-activated receptor-γ (PPARγ) activation plays an inhibitory role in this process. Objective: Until now, no data are present in literature about the involvement of CXCL9 and CXCL11 in Graves' disease and GO, or of PPARγ activators' effect on these chemokines. Methods: It has been studied how IFNγ and TNFα stimulation and PPARγ activation affect CXCL9 and CXCL11 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes. Results: In primary cultures of thyrocytes, retrobulbar fibroblasts, and retrobulbar preadipocytes obtained from GO patients, CXCL9 and CXCL11 production was absent under basal conditions; CXCL9 and CXCL11 secretion was not induced by TNFα alone, whereas it was dose dependently stimulated treating cells with IFNγ. The treatment with TNFα plus IFNγ has a synergistic effect on CXCL9 and CXCL11 release. Treating all cell types with the PPARγ agonist, rosiglitazone, or pioglitazone, the IFNγ plus TNFα-induced CXCL9 and CXCL11 release was dose dependently (0.1-20 μM) suppressed. Conclusions: We conclude that thyrocytes and retrobulbar cell types from patients with Graves' disease and ophthalmopathy participate in the self-perpetuation of inflammation, releasing CXCL9 and CXCL11 chemokines when stimulated with cytokines. PPARγ activation plays an inhibitory role in this process. The huge response of CXCL9 to the IFNγ plus TNFα-stimulation suggests its leading role among CXC chemokines. Copyright © 2009 by The Endocrine Society.