Journal of allergy and clinical immunology, 2018-01, Vol.141 (1), p.279-292
2018
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Details
- Autor(en) / Beteiligte
- Titel
- Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells
- Ist Teil von
- Journal of allergy and clinical immunology, 2018-01, Vol.141 (1), p.279-292
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2018
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Background Vitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23–driven tissue-resident group 3 innate lymphoid cells (ILC3s) play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy. Objective We set out to define the role of 1α,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3s to IL-23 plus IL-1β stimulation. Methods Transcriptomes of sorted tonsillar ILC3s were assessed by using microarray analysis. ILC3 cytokine production, proliferation, and differentiation were determined by means of flow cytometry, ELISA, and multiplex immunoassay. Intestinal cell suspensions and ILC3s sorted from gut biopsy specimens of patients with IBD were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection. Results ILC3s stimulated with IL-23 plus IL-1β upregulated the vitamin D receptor and responded to 1,25D with downregulation of the IL-23 receptor pathway. Consequently, 1,25D suppressed IL-22, IL-17F, and GM-CSF production from tonsillar and gut ILC3s. In parallel, 1,25D upregulated genes linked to the IL-1β signaling pathway, as well as the IL-1β–inducible cytokines IL-6, IL-8, and macrophage inflammatory protein 1α/β. The 1,25D-triggered skewing in ILC3 function was not accompanied or caused by changes in viability, proliferation, or phenotype. Finally, we confirmed low 25D plasma levels in patients with IBD with active inflammation. Conclusion In light of the beneficial targeting of IL-23/12 in patients with IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23 receptor pathway, providing a novel mechanism for how ILC3s could be manipulated to regulate intestinal inflammation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0091-6749, 1097-6825eISSN: 1097-6825DOI: 10.1016/j.jaci.2017.01.045Titel-ID: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_137434148
- Format
- –
- Schlagworte
- Allergy and Immunology, Biomarkers, Biopsy, Cell Proliferation, Cell Survival - genetics, Cell Survival - immunology, Cell suspensions, Chemical compounds, Cytokines, Digestive system, Digestive tract, DNA microarrays, Enzyme-linked immunosorbent assay, Flow cytometry, Gene expression, Gene Expression Profiling, Gene Expression Regulation - drug effects, Genomes, Granulocyte-macrophage colony-stimulating factor, Health risks, Homeostasis, Human behavior, Humans, IL-22, Immunoassay, Immunophenotyping, Inflammation, Inflammatory bowel disease, Inflammatory bowel diseases, Innate lymphoid cells, Interleukin 22, Interleukin 23, Interleukin 6, Interleukin 8, Intestine, Light levels, Lymphocyte Activation - immunology, Lymphocytes - immunology, Lymphocytes - metabolism, Lymphoid cells, Macrophage inflammatory protein, Macrophages, Medicin och hälsovetenskap, Mucosa, Mucous Membrane - cytology, Mucous Membrane - drug effects, Mucous Membrane - immunology, Mucous Membrane - metabolism, Plasma levels, Receptors, Calcitriol - genetics, Receptors, Calcitriol - metabolism, Receptors, Interleukin - metabolism, Risk factors, Rodents, Signal transduction, Signal Transduction - immunology, Software, Studies, Tonsil, Viability, Vitamin D, Vitamin D - pharmacology, vitamin D receptor, Vitamin D3, Vitamin deficiency