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1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a key molecule for maintaining calcium homeostasis and bone metabolism. In addition to these classic actions, 1,25(OH)2D3 has important functions in the immune system. It inhibits proinflammatory T cells such as Th1 and Th17 cells, directly inhibits interferon γ and interleukin 2 (IL2) production in CD4 T cells, induces apoptosis of B cells and inhibits immunoglobulin production. In contrast to its well-known function in the adaptive immune system, much less is known about the immunoregulatory effects of 1,25(OH)2D3 in the innate immune system, especially on activated human macrophages. The authors therefore examined the immunoregulatory effects of 1,25(OH)2D3 in human peripheral blood (PB) monocyte-derived macrophages and PMA-differentiated U937 cells.
1,25(OH)2D3 strongly stimulated the expression of IL1β in PMA-differentiated U937 cells, assessed by real-time PCR and intracellular cytokine staining. It also significantly augmented the production of IL1β in human PB monocyte-derived macrophages treated with lipopolysaccharide (LPS) or PMA. The authors found that 1,25(OH)2D3 stimulates IL1β mRNA expression by augmenting transcription, not by inhibiting mRNA degradation. The augmented expression of IL1β by 1,25(OH)2D3 was dependent on ERK1/2 activation. Parallel to the augmented expression of IL1β, 1,25(OH)2D3 increased the expression of the CCAAT enhancer-binding protein (C/ EBPβ), one of the key transcriptional regulatory factors for IL1β transcription.
The results show that 1,25(OH)2D3 modulates innate and inflammatory responses of activated macrophages by increasing IL1β expression and suggest that it may function as a proinflammatory molecule in inflammatory conditions.