Cell‐type‐specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes

Summary 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‐ κ B ( NF ‐ κ B) 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 ‐ κ B 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 ‐ κ B activation. Unexpectedly, in the same samples, vitamin D enhanced activation of both NF ‐ κ B 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 ‐ κ B 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.