Background: Anemia of chronic disease (ACD) is highly prevalent among subjects with chronic kidney disease (CKD), rheumatoid arthritis, diabetes mellitus, and cancer as well as in elderly subjects. ACD is also highly associated with infections, severe trauma and critical illness. Anemia of chronic disease is immune driven and is associated with decreased quality of life, and increased mortality. Iron is an essential nutrient for erythropoiesis and its metabolism is altered in ACD. Macrophages play a central role in iron homeostasis by engulfing senescent and damaged red blood cells (RBCs), and recycling iron daily in a process known erythrophagocytosis. Hepcidin, a master iron regulating hormone, prevents iron egress from macrophages and thus prevents normal recycling of the iron needed to support erythropoiesis. Hepcidin binds to ferroportin, the only known iron exporter, leading to its internalization and degradation and consequent iron retention in macrophages. Cytokines like IL-1β and IL-6 are commonly elevated in chronic diseases and stimulate hepcidin production from the liver and macrophages. Circulating hepcidin levels are increased in patients with chronic diseases and recently found to be inversely correlated with vitamin D status. Purpose: To investigate whether vitamin D (1,25(OH)2D) regulates the hepcidin-ferropotin axis in macrophages and thus improves iron egress to circulation to ameliorate ACD. Study design and Results: We sought to examine whether 1,25(OH)2D decreased local expression of hepcidin and increased ferroportin expression in human monocyte/macrophage cell line. THP-1 cells were cultured in the presence of increasing concentrations of 1,25(OH)2D prior to incubation with lipopolysaccharide (LPS (20ng/ml)), a known stimulator of hepcidin, to mimic an inflammatory state found in ACD. We performed RT-PCR to quantify the changes in mRNA expression in these cultured cells. We found that 1,25(OH)2D statistically decreased the mRNA expression of hepcidin and increased the expression of ferroportin in a dose dependent manner. These preliminary data strongly suggest that vitamin D plays a crucial role in macrophage recycling of iron by increasing expression of ferroportin. Although the liver is the primary source of hepcidin, we found that vitamin D also inhibited hepcidin expression in THP-1 cells. We performed in silico analysis on hepcidin promoter; however, no vitamin D response element (VDRE) consensus was identified in hepcidin promoter. Therefore, vitamin D indirectly suppresses hepcidin expression. We examined whether vitamin D may decrease inflammatory cytokines that stimulate hepcidin expression. We measured cytokine release from THP-1 cells cultured in the presence of increasing concentrations of 1,25(OH)2D prior to LPS exposure and found a dose dependent decrease in IL-1β and IL-6 release suggesting that vitamin D suppresses hepcidin expression by lowering pro-hepcidin cytokines. Conclusion: Our in vitro studies show that vitamin D regulates hepcidin-ferroportin axis in macrophages which facilitates iron egress. Thus vitamin D deficiency may contribute to the pathogenesis of ACD. To translate our finding, we are currently conducting a double-blind, randomized, placebo-controlled trial, in subjects with early chronic kidney disease supplemented with oral high dose vitamin D or matching placebo for one year.


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