Immunomodulatory effects of BXL-01-0029, a less hypercalcemic vitamin D analogue, in human cardiomyocytes and T cells
| Autor: | Erica Sarchielli, Paola Romagnani, Elisa Borgogni, Michela Francalanci, Mariangela Sottili, Lorenzo Cosmi, Mario Serio, Clara Crescioli, Elisa Ronconi, Laura Maggi, Gabriella B. Vannelli, Luciano Adorini, Francesco Annunziato |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Cell Survival medicine.medical_treatment T-Lymphocytes Blotting Western Active Transport Cell Nucleus Gene Expression Biology Pharmacology Mycophenolate Calcitriol receptor Mycophenolic acid Proinflammatory cytokine Interferon-gamma Internal medicine medicine CXCL10 Humans Myocytes Cardiac Phosphorylation Cells Cultured Cholecalciferol Receptors Interferon Cell Nucleus Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Ionomycin NF-kappa B Immunosuppression Cell Biology Mycophenolic Acid Transplantation Chemokine CXCL10 Endocrinology Cytokine STAT1 Transcription Factor Microscopy Fluorescence Receptors Calcitriol Tetradecanoylphorbol Acetate Immunosuppressive Agents medicine.drug |
| Zdroj: | Experimental cell research. 315(2) |
| ISSN: | 1090-2422 |
| Popis: | Current immunosuppressive protocols have reduced rejection occurrence in heart transplantation; nevertheless, management of heart transplant recipients is accompanied by major adverse effects, due to drug doses close to toxic range. In allograft rejection, characterized by T-helper 1 (Th1) cell-mediated response, the CXCL10-CXCR3 axis plays a pivotal role in triggering a self-promoting inflammatory loop. Indeed, CXCL10 intragraft production, required for initiation and development of graft failure, supports organ infiltration by Th1 cells. Thus, targeting the CXCL10-CXCR3 axis while avoiding generalized immunosuppression, may be of therapeutic significance. Based on preclinical evidence for immunoregulatory properties of vitamin D receptor agonists, we propose that a less hypercalcemic vitamin D analogue, BXL-01-0029, might have the potential to contribute to rejection management. We investigated the effect of BXL-01-0029 on CXCL10 secretion induced by proinflammatory stimuli, both in human isolated cardiomyocytes (Hfcm) and purified CD4+ T cells. Mycophenolic acid (MPA), the active agent of mycophenolate mofetil, was used for comparison. BXL-01-0029 inhibited IFNgamma and TNFalpha-induced CXCL10 secretion by Hfcm more potently than MPA, impairing cytokine synergy and pathways. BXL-01-0029 reduced also CXCL10 protein secretion and gene expression by CD4+ T cells. Furthermore, BXL-01-0029 did not exert any toxic effect onto both cell types, suggesting its possible use as a dose-reducing agent for conventional immunosuppressive drugs in clinical transplantation. |
| Databáze: | OpenAIRE |
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