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-alpha 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-alpha 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-alpha levels were subsequently measured. We demonstrated
a zinc concentration dependent increase in stimulated IL-1 alpha and -beta, and TNF-alpha
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-1 alpha, IL-1 beta, and TNF-alpha, 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.