Differential modulation of CXCL8 versus CXCL10, by cytokines, PPAR-gamma, or PPAR-alpha agonists, in primary cells from Graves' disease and ophthalmopathy

Silvia Martina Ferrari; Francesca Ragusa; Sabrina Rosaria Paparo; Francesco Nasini; Marco Nardi; Stefano Sellari Franceschini; Poupak Fallahi; Alessandro Antonelli

doi:10.1016/j.autrev.2019.05.004

Differential modulation of CXCL8 versus CXCL10, by cytokines, PPAR-gamma, or PPAR-alpha agonists, in primary cells from Graves' disease and ophthalmopathy

Autoimmun Rev. 2019 Jul;18(7):673-678. doi: 10.1016/j.autrev.2019.05.004. Epub 2019 May 4.

Authors

Silvia Martina Ferrari¹, Francesca Ragusa¹, Sabrina Rosaria Paparo¹, Francesco Nasini², Marco Nardi³, Stefano Sellari Franceschini⁴, Poupak Fallahi¹, Alessandro Antonelli⁵

Affiliations

¹ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
² Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
³ Department of Surgical, Medical and Molecular Pathology, Ophthalmopathy Unit I, University of Pisa and University Hospital of Pisa, Pisa, Italy.
⁴ Department of Surgical, Medical and Molecular Pathology, ENT Unit I, University of Pisa and University Hospital of Pisa, Pisa, Italy.
⁵ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. Electronic address: alessandro.antonelli@med.unipi.it.

PMID: 31059842
DOI: 10.1016/j.autrev.2019.05.004

Abstract

Background: Thyrocytes secrete CXC chemokines, particularly (C-X-C motif) ligand (CXCL)8 and CXCL10; its physiopathological significance remains unclear. This study investigates the modulation of the secretion of CXCL8 vs. CXCL10, in human primary cells cultures of thyroid follicular cells (TFC) in Graves' disease (GD), and fibroblasts (OF) or preadipocytes (OP) from Graves' ophthalmopathy (GO).

Methods: Cells were initially incubated with different concentrations of tumor necrosis factor (TNF)α (1, 5, 10 ng/mL). Then, CXCL8 and CXCL10 were measured in the supernatants of TFC, OF or OP cells basally and after 24 h of treatment with interferon (IFN)γ (1000 IU/mL) and/or TNFα (10 ng/mL), in presence/absence of the peroxisome proliferator activated receptor (PPAR)γ agonist pioglitazone (0, 0.1, 1, 5, 10, 20 μM), or the PPARα agonist fenofibrate (5, 10, 50, 100 μM).

Results: CXCL8, not CXCL10, was detected in basal conditions in TFC, OF and OP. CXCL8 secretion increased dose-dependently with increasing concentrations of TNFα. CXCL10 secretion was significantly stimulated by IFNγ (P < 0.01) and not by TNFα, whereas CXCL8 was induced by TNFα (P < 0.01), and inhibited by IFNγ (P < 0.01) in TFC, OF and OP. Combining TNFα and IFNγ, the IFNγ-induced CXCL10 secretion was synergistically increased (P < 0.01) while the TNFα-induced CXCL8 secretion (P < 0.01) was reversed in all cell types. Pioglitazone had no significant effect on the secretion of CXCL8 stimulated by TNFα, while inhibited CXCL10. Fenofibrate, in presence of IFNγ plus TNFα, dose-dependently inhibited both CXCL10 and CXCL8 release.

Conclusion: We first show that TFC, OF, and OP secrete CXCL8 and CXCL10 differentially, sustained by specific proinflammatory cytokines or their combination. This could reflect a different role of the two chemokines in the course of the disease, as CXCL10 could be associated with the initial phase of the disease when IFNγ is preponderant, while CXCL8 could be associated with a later chronic phase of the disease, when TNFα prevails.

Keywords: CXCL10; CXCL8; Fibroblasts; Graves' disease; Graves' ophthalmopathy; Thyrocytes.

MeSH terms

Adipocytes / immunology*
Cells, Cultured
Cytokines / immunology*
Fibroblasts / immunology*
Graves Disease / immunology*
Graves Ophthalmopathy / immunology*
Humans
PPAR gamma / immunology*
Thyroid Epithelial Cells / immunology*

Substances

Cytokines
PPAR gamma