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.