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 b chemokine (C-C motif) ligand 2 (CCL2) or of peroxisome proliferator-activated receptor a (PPARa (PPARA)) activation on CCL2 and CXCL10 chemokines secretion in fibroblasts or preadipocytes in Graves' ophthalmopathy (GO). We have tested the effect of interferon g (IFNg (IFNG)) and tumor necrosis factor a (TNFa) on CCL2, and for comparison on the prototype a chemokine (C-X-C motif) ligand 10 (CXCL10), and the possible modulatory role of PPARa activation on secretion of these chemokines in normal and GO fibroblasts or preadipocytes in primary cell cultures. This study shows that IFNg alone, or in combination with TNFa, stimulates the secretion of CCL2 in primary orbital fibroblasts or preadipocytes from patients with GO at levels similar to those observed in controls. IFNg and TNFa also stimulated CXCL10 chemokine secretion as expected. The presence of PPARa and PPARg (PPARG) in primary fibroblasts or preadipocytes of patients with GO has been confirmed. PPARa activators were able to inhibit the secretion of CXCL10 and CCL2, while PPARg activators were confirmed to be able to inhibit CXCL10 but had no effect on CCL2. PPARa activators were stronger inhibitors of chemokine secretions than PPARg agonists. In conclusion, CCL2 and CXCL10 are modulated by IFNg and TNFa in GO. PPARa activators inhibit the secretion of the main prototype a (CXCL10) and b (CCL2) chemokines in GO fibroblasts or preadipocytes, suggesting that PPARa may be involved in the modulation of the immune response in GO.

Euthyroid Graves’ orbitopathy and incidental papillary thyroid microcarcinoma

“…44,45 Recent research has shown that peroxisome proliferator-activated receptor-α (PPARα) agonists may exert immunomodulatory effects in GO by inhibiting various chemokines secreted by GO fibroblasts and preadipocytes. 46,47 Perhaps addressing this pathogenic mechanism will help reduce the chance of disease recurrence in the future.…”

Graves ophthalmopathy: low-dose glucocorticoid increases peroxisome proliferator-activated receptor-gamma gene expression

“…From this point of view, lower glucocorticoid doses would imply a smaller PPAR-g-mediated inflammatory response. However, there has been evidence suggesting that the anti-inflammatory potential of this receptor activation would not be as significant as that of other receptors from the same family, such as PPAR-α (4) . Therefore, considering the preponderant action of PPAR-g on adipogenesis, when opting for glucocorticoids in the treatment of GO, we could speculate that the ideal would be not using low doses, which would stimulate expression of the receptor, increasing the adipocyte differentiation and contributing to progression of the exophthalmos.…”

“…Another point of concern has been the inflammatory response, a result of the release by monocytes and macrophages of cytokines and other mediators, which can contribute significantly to the progression of the condition and implies that corticotherapy should be the main therapeutic approach (3) . Unlike what happens in the adipocyte pathway, PPAR-g activation has been associated with inhibition of the inflammatory process induced by certain cytokines (4) , which raises doubts about the final balance of receptor stimulation regarding the evolution of GO. Furthermore, the possible relation of PPAR-g with the treatment of an ocular condition with glucocorticoids remain to be clarified.…”

“…Thus, considering the importance of the PPAR-g receptor to the adipocyte (1,2) , one could assume that using lower doses of glucocorticoids when treating GO would imply greater gene expression and greater adipocyte differentiation in the orbital fibroblasts, with worsening of proptosis. On the other hand, PPAR-g activation plays an inhibitory role on the inflammatory process (4) . From this point of view, lower glucocorticoid doses would imply a smaller PPAR-g-mediated inflammatory response.…”

CXC-Chemokines and Thyroid Associated Autoimmunity

“…Also orbital fibroblasts and preadipocytes from patients with Graves' ophthalmopathy are able to secrete CXCL10, CXCL9, and CXCL11 chemokines, under the influence of IFN-γ, and the combination of IFN-γ and tumor necrosis factor (TNF)-α [7][8][9].…”