title: β (CCL2) and α (CXCL10) chemokine modulations by cytokines and peroxisome proliferator-activated receptor-α agonists in Graves' ophthalmopathy.
abstract: No data are present in the literature about the effect of cytokines on the prototype β chemokine (C-C motif) ligand 2 (CCL2) or of peroxisome proliferator-activated receptor α (PPARα (PPARA)) activation on CCL2 and CXCL10 chemokines secretion in fibroblasts or preadipocytes in Graves' ophthalmopathy (GO). We have tested the effect of interferon γ (IFNγ (IFNG)) and tumor necrosis factor α (TNFα) on CCL2, and for comparison on the prototype α chemokine (C-X-C motif) ligand 10 (CXCL10), and the possible modulatory role of PPARα activation on secretion of these chemokines in normal and GO fibroblasts or preadipocytes in primary cell cultures. This study shows that IFNγ alone, or in combination with TNFα, stimulates the secretion of CCL2 in primary orbital fibroblasts or preadipocytes from patients with GO at levels similar to those observed in controls. IFNγ and TNFα also stimulated CXCL10 chemokine secretion as expected. The presence of PPARα and PPARγ (PPARG) in primary fibroblasts or preadipocytes of patients with GO has been confirmed. PPARα activators were able to inhibit the secretion of CXCL10 and CCL2, while PPARγ activators were confirmed to be able to inhibit CXCL10 but had no effect on CCL2. PPARα activators were stronger inhibitors of chemokine secretions than PPARγ agonists. In conclusion, CCL2 and CXCL10 are modulated by IFNγ and TNFα in GO. PPARα activators inhibit the secretion of the main prototype α (CXCL10) and β (CCL2) chemokines in GO fibroblasts or preadipocytes, suggesting that PPARα may be involved in the modulation of the immune response in GO.
authors.affiliation: Department of Internal Medicine, School of Medicine, University of Pisa, Via Roma 67, I-56100 Pisa, Italy. alessandro.antonelli@med.unipi.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Antonelli
authors.forename: Silvia Martina
authors.initials: SM
authors.lastname: Ferrari
authors.forename: Silvia
authors.initials: S
authors.lastname: Frascerra
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ruffilli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pupilli
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Bernini
authors.forename: Stefano
authors.initials: S
authors.lastname: Sellari-Franceschini
authors.forename: Stefania
authors.initials: S
authors.lastname: Gelmini
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
authors.forename: Poupak
authors.initials: P
authors.lastname: Fallahi
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D049970:Graves Ophthalmopathy / Q000503:physiopathology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000378:metabolism / Q000494:pharmacology; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D007371:Interferon-gamma; D011345:Fenofibrate; D000077205:Pioglitazone