title: Elocalcitol inhibits inflammatory responses in human thyroid cells and T cells.
abstract: 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)gamma 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 IFNgamma and TNFalpha-induced CXCL10 protein secretion more potently than MMI. Elocalcitol impaired both cytokine intracellular pathways, whereas MMI was effective only on the IFNgamma 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.
authors: Department of Clinical Pathophysiology, Unit of Endocrinology, University of Florence, Viale Pieraccini 6, Florence, Italy.
authors: E
authors: E
authors: Borgogni
authors: E
authors: E
authors: Sarchielli
authors: M
authors: M
authors: Sottili
authors: V
authors: V
authors: Santarlasci
authors: L
authors: L
authors: Cosmi
authors: S
authors: S
authors: Gelmini
authors: A
authors: A
authors: Lombardi
authors: G
authors: G
authors: Cantini
authors: G
authors: G
authors: Perigli
authors: M
authors: M
authors: Luconi
authors: G B
authors: GB
authors: Vannelli
authors: F
authors: F
authors: Annunziato
authors: L
authors: L
authors: Adorini
authors: M
authors: M
authors: Serio
authors: C
authors: C
authors: Crescioli
mesh_terms: D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008713:Methimazole / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017471:Receptors, Interferon / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C487049:BXL628; D054357:Chemokine CXCL10; D018836:Inflammation Mediators; D016328:NF-kappa B; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D008713:Methimazole; D002117:Calcitriol