Vitamin D anti-inflammatory pathway uncovered
MedWire News: US researchers have discovered a novel pathway by which vitamin D inhibits inflammation.
The findings, derived from a series of complex in vitro experiments, support current suggestions that vitamin D plays an important role in inflammatory diseases.
"This study goes beyond previous associations of vitamin D with various health outcomes. It outlines a clear chain of cellular events, from the binding of DNA, through a specific signaling pathway, to the reduction of proteins known to trigger inflammation," said lead author Elena Goleva (National Jewish Health, Denver, Colorado) in a press statement.
The researchers investigated the role of vitamin D in the regulation of lipopolysaccharide (LPS)-stimulated inflammatory response in human blood monocytes.
They incubated the monocytes with varying levels of 25(OH)D3 (the circulating form of vitamin D) and 1,25(OH)2D3 (the active form of vitamin D) for 24 hours then stimulated them with 10 ng/mL LPS.
They observed that both forms of vitamin D dose-dependently inhibited LPS-induced phosphorylation of the mitogen-activated protein kinase (MAPK) p38. This in turn resulted in decreased production of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α.
Of note, incubation with 15 ng/mL 25(OH)D3 - a level that indicates vitamin D deficiency in humans - did not suppress LPS-induced p38 phosphorylation or production of IL-6 and TNF-α, whereas significant inhibition was achieved with 25(OH)D3 levels at or above 30 ng/mL, which is considered sufficient in humans. The highest levels of inflammatory inhibition occurred at 50 ng/mL.
Next, the researchers discovered that vitamin D pretreatment upregulates expression of MAPK phosphatase-1 (MKP-1) in human monocytes and murine bone marrow-derived macrophages (BMM). They explain that this protein plays a critical role in switching off p38 signaling and cytokine production in monocytes and macrophages after inflammatory stimulation.
The team also showed that vitamin D treatment increased binding of the vitamin D receptor to a putative vitamin D response element (VDRE) that they identified in both the human and murine MKP-1 promoter near the VDRE site.
Moreover, the inhibition of LPS-induced p38 phosphorylation by vitamin D was completely abolished, and inhibition of LPS-induced IL-6 and TNF-α was reduced, in MKP-1 knockout mice.
Writing in the Journal of Immunology, the researchers say that their study "identified the upregulation of MKP-1 by vitamin D as a novel pathway by which vitamin D inhibits LPS-induced p38 activation and cytokine production in monocytes/macrophages."
Goleva added: "This newly identified DNA-binding site for the vitamin-D receptor, and the specific pathways inhibited by higher levels of vitamin D provide a plausible mechanism for many of the benefits that have been associated with vitamin D. The fact that we showed a dose-dependent and varying response to levels commonly found in humans also adds weight to the argument for vitamin D's role in immune and inflammatory conditions.
"Patients with chronic inflammatory diseases, such as asthma, arthritis and prostate cancer, who are vitamin D deficient, may benefit from vitamin D supplementation to get their serum vitamin D levels above 30 ng/mL," she concluded.
By Laura Cowen