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Monokine Induced by Interferon (IFN) (CXCL9) and IFN Inducible T-Cell -Chemoattractant (CXCL11) Involvement in Graves’ Disease and Ophthalmopathy: Modulation by Peroxisome Proliferator-Activated Receptor- Agonists

Departments of Internal Medicine (A.A., S.M.F., P.F., S.F., E.S., E.F.) and Otorhinolaryngology (S.S.F.), University of Pisa-School of Medicine, I-56100 Pisa, Italy

Address all correspondence and requests for reprints to: Alessandro Antonelli, M.D., 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/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 (IFN) and TNF. Peroxisome proliferator-activated receptor- (PPAR) 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 activators’ effect on these chemokines.

Methods: It has been studied how IFN and TNF stimulation and PPAR 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 alone, whereas it was dose dependently stimulated treating cells with IFN. The treatment with TNF plus IFN has a synergistic effect on CXCL9 and CXCL11 release. Treating all cell types with the PPAR agonist, rosiglitazone, or pioglitazone, the IFN plus TNF-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. PPAR activation plays an inhibitory role in this process. The huge response of CXCL9 to the IFN plus TNF-stimulation suggests its leading role among CXC chemokines.