BACKGROUND: Local production of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) regulated by the CYP27B1 enzyme in monocytes contributes to the immunomodulatory effects of vitamin D. Uremia suppresses renal CYP27B1, but its impact on monocytic CYP27B1 is incompletely understood. The present study aimed to elucidate this issue and to define the pathogenic role of p-cresyl sulfate (PCS), indoxyl sulfate (IndS), and fibroblast growth factor 23 (FGF23). METHODS: Resting or immune (interferon-γ + lipopolysaccharide)-stimulated THP1 cells and monocytes, isolated from healthy donors, were cultured in the presence of either healthy serum, uremic serum, PCS, IndS or FGF23. RNA expression levels for CYP27B1 and cytokines were quantified by RT-PCR and enzymatic CYP27B1 activity was measured 24 h after incubation. RESULTS: Culturing THP1 cells or human monocytes in the presence of uremic serum led to higher inflammatory cytokine and CYP27B1 expression. Immune signal-induced CYP27B1 expression and activity, conversely, was impaired in the presence of uremic serum. Similar effects were observed in the presence of FGF23, although significance was reached in immune-stimulated cells only. PCS and IndS failed to show any effect. CONCLUSIONS: Monocytic baseline CYP27B1 expression is increased in uremia, probably reflecting the microinflammatory state. Immune signal-induced CYP27B1 expression, conversely, is impaired in uremic conditions. Elevated FGF23 levels, but not PCS and IndS, may account, at least partly, for the dysregulation of monocytic CYP27B1 in uremia and, as such, may contribute to the high cardiovascular and infectious burden in chronic kidney disease.
BACKGROUND: Local production of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) regulated by the CYP27B1 enzyme in monocytes contributes to the immunomodulatory effects of vitamin D. Uremia suppresses renal CYP27B1, but its impact on monocytic CYP27B1 is incompletely understood. The present study aimed to elucidate this issue and to define the pathogenic role of p-cresyl sulfate (PCS), indoxyl sulfate (IndS), and fibroblast growth factor 23 (FGF23). METHODS: Resting or immune (interferon-γ + lipopolysaccharide)-stimulated THP1 cells and monocytes, isolated from healthy donors, were cultured in the presence of either healthy serum, uremic serum, PCS, IndS or FGF23. RNA expression levels for CYP27B1 and cytokines were quantified by RT-PCR and enzymatic CYP27B1 activity was measured 24 h after incubation. RESULTS: Culturing THP1 cells or human monocytes in the presence of uremic serum led to higher inflammatory cytokine and CYP27B1 expression. Immune signal-induced CYP27B1 expression and activity, conversely, was impaired in the presence of uremic serum. Similar effects were observed in the presence of FGF23, although significance was reached in immune-stimulated cells only. PCS and IndS failed to show any effect. CONCLUSIONS: Monocytic baseline CYP27B1 expression is increased in uremia, probably reflecting the microinflammatory state. Immune signal-induced CYP27B1 expression, conversely, is impaired in uremic conditions. Elevated FGF23 levels, but not PCS and IndS, may account, at least partly, for the dysregulation of monocytic CYP27B1 in uremia and, as such, may contribute to the high cardiovascular and infectious burden in chronic kidney disease.
Authors: Jan Rossaint; Jessica Oehmichen; Hugo Van Aken; Stefan Reuter; Hermann J Pavenstädt; Melanie Meersch; Mark Unruh; Alexander Zarbock Journal: J Clin Invest Date: 2016-02-15 Impact factor: 14.808
Authors: Raymond Vanholder; Eva Schepers; Anneleen Pletinck; Evi V Nagler; Griet Glorieux Journal: J Am Soc Nephrol Date: 2014-05-08 Impact factor: 10.121