Monokine induced by interferon gamma (IFNgamma) (CXCL9) and IFNgamma inducible T-cell alpha-chemoattractant (CXCL11) involvement in Graves' disease and ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists.
BACKGROUND
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 (IFNgamma) and TNFalpha. Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma activators' effect on these chemokines.


METHODS
It has been studied how IFNgamma and TNFalpha stimulation and PPARgamma 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 TNFalpha alone, whereas it was dose dependently stimulated treating cells with IFNgamma. The treatment with TNFalpha plus IFNgamma has a synergistic effect on CXCL9 and CXCL11 release. Treating all cell types with the PPARgamma agonist, rosiglitazone, or pioglitazone, the IFNgamma plus TNFalpha-induced CXCL9 and CXCL11 release was dose dependently (0.1-20 microm) 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. PPARgamma activation plays an inhibitory role in this process. The huge response of CXCL9 to the IFNgamma plus TNFalpha-stimulation suggests its leading role among CXC chemokines.
Antonelli
Alessandro
A
Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma, 67, I-56100 Pisa, Italy. a.antonelli@med.unipi.it
Ferrari
Silvia Martina
SM
Fallahi
Poupak
P
Frascerra
Silvia
S
Santini
Eleonora
E
Franceschini
Stefano Sellari
SS
Ferrannini
Ele
E
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D054371:Chemokine CXCL11 / Q000096:biosynthesis*; D054370:Chemokine CXCL9 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006111:Graves Disease / Q000378:metabolism*; D049970:Graves Ophthalmopathy / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D007371:Interferon-gamma; D000077205:Pioglitazone