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Interferon--Inducible -Chemokine CXCL10 Involvement in Graves’ Ophthalmopathy: Modulation by Peroxisome Proliferator-Activated Receptor- Agonists

Department of Medicine (A.A., S.M.F., P.F., E.F.) and Otorhinolaryngology Unit (S.S.F.), University of Pisa School of Medicine, I-56100 Pisa, Italy; Department of Clinical and Experimental Medicine and Surgery F. Magrassi–A. Lanzara, Second University of Naples (M.R.), 80100 Naples, Italy; and Department of Clinical Pathophysiology, Endocrinology Unit, University of Florence (P.R., M.S.), 50100 Florence, Italy

Address all correspondence and requests for reprints to: Dr. Alessandro Antonelli, Department of Internal Medicine, University of Pisa School of Medicine, Via Roma 67, I-56100 Pisa, Italy. E-mail: a.antonelli{at}med.unipi.it.

Context: CXC -chemokine CXCL10/inducing protein-10 play an important role in the initial phases of autoimmune thyroid disorders. Human thyrocytes in primary culture produce large amounts of CXCL10 when stimulated by interferon- (IFN) and TNF.

Objective: Serum CXCL10 levels (sCXCL10) were measured in patients with active or inactive Graves’ ophthalmopathy (GO). The effects of IFN and TNF stimulation and peroxisome proliferator-activated receptor- (PPAR) activation on CXCL10 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes were tested.

Patients: Sixty consecutive patients with Graves’ disease, 60 age- and sex-matched patients with GO, and 60 controls were studied.

Results: sCXCL10 was higher (P < 0.0001) in Graves’ disease (120 ± 83 pg/ml; n = 60) and GO (122 ± 71; n = 60) patients than in age- and sex-matched euthyroid controls (72 ± 32; n = 60). Among GO patients, sCXCL10 levels were significantly higher in those (n = 14) with active disease (171 ± 197) than in those with inactive disease (114 ± 45 pg/ml; P < 0.003). In primary cultures of thyrocytes, retrobulbar fibroblasts and retrobulbar preadipocytes from GO patients, CXCL10 production was absent under basal conditions; dose-dependent secretion of CXCL10 was not induced by TNF alone, whereas stimulation with IFN or TNF plus IFN induced CXCL10 release. Treatment of all cell types with the PPAR agonist, rosiglitazone, dose-dependently (0.1–10 µM) suppressed IFN- plus TNF-induced CXCL10 release.

Conclusions: We conclude that in GO, thyrocytes and retrobulbar cell types participate in the self-perpetuation of inflammation by releasing chemokines under the influence of cytokines. PPAR activation plays an inhibitory role in this process.

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