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

Context: CXC alpha-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 gamma(IFN gamma) and TNF alpha. Peroxisome proliferator-activated receptor-gamma(PPAR gamma) 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 PPAR gamma activators' effect on these chemokines. Methods: It has been studied how IFN gamma and TNF alpha stimulation and PPAR gamma 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 TNF alpha alone, whereas it was dose dependently stimulated treating cells with IFN gamma. The treatment with TNF alpha plus IFN gamma has a synergistic effect on CXCL9 and CXCL11 release. Treating all cell types with the PPAR gamma agonist, rosiglitazone, or pioglitazone, the IFN gamma plus TNF alpha-induced CXCL9 and CXCL11 release was dose dependently (0.1-20 mu M) 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. PPAR gamma activation plays an inhibitory role in this process. The huge response of CXCL9 to the IFN gamma plus TNF alpha-stimulation suggests its leading role among CXC chemokines. (J Clin Endocrinol Metab 94: 1803-1809, 2009)