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 (VDR) agonists exhibit anti-inflammatory properties and promote tolerance induction.

We investigated the effects and the mechanism of action of a non hypercalcemic VDR agonist, elocalcitol (BXL-628), compared to 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 cytokines intracellular pathways, while 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 towards a Th2 response.

In conclusion, elocalcitol could represent a novel pharmacological tool in the treatment of autoimmune thyroid diseases.