TY - JOUR
T1 - Zinc modulates mononuclear cellular calcitriol metabolism in peritoneal dialysis patients
AU - Kimmel, Paul L.
AU - Phillips, Terry M.
AU - Lew, Susie Q.
AU - Langman, Craig B.
N1 - Funding Information:
These studies were supported by grants from the Biomedical Research Support Grants program of the National Institutes of Health, from the National Capital Chapter of the National Kidney Foundation, and the Children's Memorial Institute for Education and Research. We appreciate the assistance of Samuel J. Simmens, Ph.D. of the Public Health Program, George Washington University Medical Center, in analyzing data.
PY - 1996
Y1 - 1996
N2 - Zinc has long been known to play a role in maintaining immunologic function. Hypozincemia, however, is common in patients with end-stage renal disease (ESRD) treated with continuous ambulatory peritoneal dialysis (CAPD). We previously demonstrated that zinc depletion limits the ability of animals to achieve maximum circulating calcitriol levels in response to the stress of calcium or phosphorus depletion. It was unclear, however, whether changes in the circulating levels of calcitriol in these settings was associated with a direct effect on renal 1-α hydroxylase activity, or whether the zinc dependence of the stimulated calcitriol response involved an integrated systemic response in intact animals. In addition it was unclear whether circulating zinc levels or zinc nutritional status modified calcitriol metabolism in humans. To better understand the role zinc plays in the immune response in patients with ESRD, we studied IL-1, calcitriol and tumor necrosis factor-α production by mononuclear cells from blood and peritoneal effluents of 22 patients with ESRD treated with CAPD. Macrophages from peritoneal effluents and peripheral blood mononuclear cells were isolated and pulsed with phytohemagglutinin in medium to which different concentrations of zinc chloride, copper chloride, and carbonyl cyanide p-(trifluoromethoxy)phenyl-hydrazone (FCCP), an inhibitor of mitochondrial function were added. Supernatant interleukin-1, calcitriol, and tumor necrosis factor-α levels were subsequently measured. We demonstrated a zinc concentration dependent increase in stimulated IL-1α and -β, and TNF-α release in both peripheral mononuclear cells and peritoneal macrophages from patients with ESRD treated with CAPD. The effect is zinc specific, as it is not reproduced by copper or chloride supplementation. A zinc concentration dependent increase in peritoneal macrophage calcitriol release was also noted. FCCP blocked the cellular production of IL-1α, IL-1β, and TNF-α, but had little effect on zinc-induced stimulated mononuclear cell supernatant calcitriol levels. The different shape of the zinc dose response curve, and the lack of correlation between paired IL-1 and calcitriol supernatant levels suggests the effect of zinc on mononuclear cellular cytokine and calcitriol production is mediated through different pathways.
AB - Zinc has long been known to play a role in maintaining immunologic function. Hypozincemia, however, is common in patients with end-stage renal disease (ESRD) treated with continuous ambulatory peritoneal dialysis (CAPD). We previously demonstrated that zinc depletion limits the ability of animals to achieve maximum circulating calcitriol levels in response to the stress of calcium or phosphorus depletion. It was unclear, however, whether changes in the circulating levels of calcitriol in these settings was associated with a direct effect on renal 1-α hydroxylase activity, or whether the zinc dependence of the stimulated calcitriol response involved an integrated systemic response in intact animals. In addition it was unclear whether circulating zinc levels or zinc nutritional status modified calcitriol metabolism in humans. To better understand the role zinc plays in the immune response in patients with ESRD, we studied IL-1, calcitriol and tumor necrosis factor-α production by mononuclear cells from blood and peritoneal effluents of 22 patients with ESRD treated with CAPD. Macrophages from peritoneal effluents and peripheral blood mononuclear cells were isolated and pulsed with phytohemagglutinin in medium to which different concentrations of zinc chloride, copper chloride, and carbonyl cyanide p-(trifluoromethoxy)phenyl-hydrazone (FCCP), an inhibitor of mitochondrial function were added. Supernatant interleukin-1, calcitriol, and tumor necrosis factor-α levels were subsequently measured. We demonstrated a zinc concentration dependent increase in stimulated IL-1α and -β, and TNF-α release in both peripheral mononuclear cells and peritoneal macrophages from patients with ESRD treated with CAPD. The effect is zinc specific, as it is not reproduced by copper or chloride supplementation. A zinc concentration dependent increase in peritoneal macrophage calcitriol release was also noted. FCCP blocked the cellular production of IL-1α, IL-1β, and TNF-α, but had little effect on zinc-induced stimulated mononuclear cell supernatant calcitriol levels. The different shape of the zinc dose response curve, and the lack of correlation between paired IL-1 and calcitriol supernatant levels suggests the effect of zinc on mononuclear cellular cytokine and calcitriol production is mediated through different pathways.
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U2 - 10.1038/ki.1996.198
DO - 10.1038/ki.1996.198
M3 - Article
C2 - 8731107
AN - SCOPUS:0029973325
VL - 49
SP - 1407
EP - 1412
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 5
ER -