Vitamin D enhances glucocorticoid action in human monocytes: involvement of granulocyte-macrophage colony-stimulating...

Vitamin D (VitD) is now recognized for its pleiotrophic roles in regulating immune function. VitD interaction with other steroid receptor superfamily receptors in peripheral blood mononuclear cells is poorly understood. In the current study, we demonstrate that VitD enhanced glucocorticoid (GC) responses in human peripheral blood mononuclear cells because it stimulated GC induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) and enhanced GC inhibition of LPS-induced IL-6. These VitD effects were abolished in purified CD14(+) and CD14(-) cells but were recovered in CD14(+) cells co-cultured with CD14(-) cells separated by tissue culture inserts. GM-CSF, found in culture supernatants from CD14(-) cells, was shown to mediate VitD enhancement of GC-induced MKP-1 production in monocytes via increased production of mediator complex subunit 14 (MED14). Recruitment of VitD receptor and MED14, 4.7 kbp upstream of the human MKP-1 gene transcription start site, enhanced binding of glucocorticoid receptor and histone H4 acetylation at the 4.6-kbp glucocorticoid response element of the MKP-1 promoter in the presence of GM-CSF in U937 cells. Knockdown of MED14 abolished VitD-mediated enhancement of GC-induced MKP-1 production. These data demonstrate VitD-mediated stimulation of GC anti-inflammatory effects in human monocytes and identify a role for GM-CSF and MED14 as mediators of this process.