Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves' ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists.
BACKGROUND
CXC alpha-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-gamma (IFNgamma) and TNFalpha.


OBJECTIVE
Serum CXCL10 levels (sCXCL10) were measured in patients with active or inactive Graves' ophthalmopathy (GO). The effects of IFNgamma and TNFalpha stimulation and peroxisome proliferator-activated receptor-gamma (PPARgamma) activation on CXCL10 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes were tested.


METHODS
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 TNFalpha alone, whereas stimulation with IFNgamma or TNFalpha plus IFNgamma induced CXCL10 release. Treatment of all cell types with the PPARgamma agonist, rosiglitazone, dose-dependently (0.1-10 microm) suppressed IFNgamma- plus TNFalpha-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. PPARgamma activation plays an inhibitory role in this process.
Antonelli
Alessandro
A
Department of Internal Medicine, University of Pisa School of Medicine, Via Rome 67, I-56100 Pisa, Italy. a.antonelli@med.unipi.it
Rotondi
Mario
M
Ferrari
Silvia Martina
SM
Fallahi
Poupak
P
Romagnani
Paola
P
Franceschini
Stefano Sellari
SS
Serio
Mario
M
Ferrannini
Ele
E
D000328:Adult; D002454:Cell Differentiation / Q000502:physiology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000097:blood* / Q000378:metabolism; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology; D049970:Graves Ophthalmopathy / Q000097:blood / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D013601:T-Lymphocytes / Q000276:immunology; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D005343:Fibrinolytic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D007371:Interferon-gamma