Cell-type-specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes.
Vitamin D is widely reported to inhibit innate immune signalling and dendritic cell (DC) maturation as a potential immunoregulatory mechanism. It is not known whether vitamin D has global or gene-specific effects on transcriptional responses downstream of innate immune stimulation, or whether vitamin D inhibition of innate immune signalling is common to different cells. We confirmed vitamin D inhibition of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signalling in monocyte-derived DC (MDDC) stimulated with lipopolysaccharide (LPS). This was associated with global but modest attenuation of LPS-induced transcriptional changes at genome-wide level. Surprisingly, vitamin D did not inhibit innate immune NF-κB activation in monocyte-derived macrophages. Consistent with our findings in MDDC, ex vivo vitamin D treatment of primary peripheral blood myeloid DC also led to significant inhibition of LPS-inducible NF-κB activation. Unexpectedly, in the same samples, vitamin D enhanced activation of both NF-κB and MAPK signalling in primary peripheral blood monocytes. In a cross-sectional clinical cohort, we found no relationship between peripheral blood vitamin D levels and LPS-inducible activation of NF-κB and MAPK pathways in monocytes of myeloid DC. Remarkably, however, in vivo supplementation of people with vitamin D deficiency in this clinical cohort also enhanced LPS-inducible MAPK signalling in peripheral blood monocytes. Therefore, we report that vitamin D differentially modulates the molecular response to innate immune stimulation in monocytes, macrophages and dendritic cells. These results are of importance in the design of studies on vitamin D supplementation in infectious and immunological diseases.
Division of Infection and Immunity, University College London, London, UK.
Rhiannon
R
Kundu
Endocrinology, Division of Medicine, University College London, London, UK.
Aikaterini
A
Theodoraki
Division of Infection and Immunity, University College London, London, UK.
Carolin T
CT
Haas
Division of Infection and Immunity, University College London, London, UK.
Yanjing
Y
Zhang
Division of Infection and Immunity, University College London, London, UK.
Benjamin
B
Chain
MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
Janos
J
Kriston-Vizi
Division of Infection and Immunity, University College London, London, UK.
Mahdad
M
Noursadeghi
Endocrinology, Division of Medicine, University College London, London, UK.
Bernard
B
Khoo
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D015331:Cohort Studies; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity; D015398:Signal Transduction / Q000187:drug effects; D014807:Vitamin D / Q000627:therapeutic use*; D014808:Vitamin D Deficiency / Q000188:drug therapy* / Q000276:immunology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D014807:Vitamin D; D048051:p38 Mitogen-Activated Protein Kinases
dendritic cells; macrophages; mitogen-activated protein kinase; monocytes; nuclear factor-κB; vitamin D