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Elocalcitol Inhibits Inflammatory Responses in Human Thyroid Cells and T Cells

Departments of Clinical Pathophysiology (E.B., M.So., S.G., A.L., G.C., M.L., M.Se., C.C.) and Internal Medicine (V.S., L.C., F.A.), Center for Research Transfer and High Education "DENOthe" (De Novo Therapies), Department of Anatomy, Histology and Forensic Medicine (E.S., G.B.V.), General Surgery Medical School (G.P.), University of Florence, 6-50139 Florence, Italy; and BioXell (L.A.), 20132 Milan, Italy

Address all correspondence and requests for reprints to: Dr. Clara Crescioli, Department of Clinical Pathophysiology, Unit of Endocrinology, University of Florence, Viale Pieraccini, 6-50139 Florence, Italy. E-mail: c.crescioli{at}dfc.unifi.it.

T-helper 1 (Th1) cell-mediated inflammatory responses predominate in the early pathogenesis of Graves’ disease (GD), whereas Th2 cell-mediated immunity may play a role in later stages. The chemokine CXCL10 and its receptor CXCR3 are expressed in most thyroid glands of early GD patients. Circulating CXCL10 levels inversely correlate with disease duration; CXCL10 maximal expression also correlates with interferon (IFN) levels in recent GD onset. Methimazole (MMI) reduces CXCL10 secretion by isolated thyrocytes, decreases serum CXCL10 levels, and promotes a transition from Th1 to Th2 dominance in patients in GD active phase. Vitamin D receptor agonists exhibit antiinflammatory properties and promote tolerance induction. We investigated the effects and the mechanism of action of a nonhypercalcemic vitamin D receptor agonist, elocalcitol (BXL-628), compared with MMI on CXCL10 secretion induced by proinflammatory cytokines. Furthermore, we studied the effects of both drugs on Th1, Th17, and Th2 cytokine secretion in CD4+ T cells. ELISA, cytometry, immunocytochemistry, Western blot, and quantitative real-time PCR were used for protein and gene analysis. In human thyrocytes, elocalcitol inhibited IFN and TNF-induced CXCL10 protein secretion more potently than MMI. Elocalcitol impaired both cytokine intracellular pathways, whereas MMI was effective only on the IFN pathway. In CD4+ T cells, elocalcitol decreased Th1- and Th17-type cytokines, and promoted Th2-type cytokine secretion. Elocalcitol and MMI inhibited Th1 cytokine-mediated responses in thyrocytes and CD4+ T cells. In addition, elocalcitol promoted a shift toward a Th2 response. In conclusion, elocalcitol could represent a novel pharmacological tool in the treatment of autoimmune thyroid diseases.

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