The Danger Within

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Abstract
Jerome and Corey (Jan. 22 issue)1 comment on the identification of urate crystals as an immunologic danger signal released from apoptotic cells in mice, as shown in part by the ability of purified urate crystals to induce maturation of dendritic cells in vitro (when cultured in 10 percent fetal-calf serum).2 Inconsistent with this proposed signal is the finding that humans lacking xanthine oxidase, and hence urate, have no known immunologic disorder.3 Because mice and cattle (but not humans) express urate oxidase (uricase), we wondered whether the hydrogen peroxide produced by uricase in fetal-calf serum might be responsible for effects attributed to urate crystals. Urate crystals induced maturation of dendritic cells that were cultured in fetal-calf serum, but not those cultured in human serum. Incubating dendritic cells with urate crystals in fetal-calf serum, but not in human serum, resulted in the production of reactive oxygen species. Adding hydrogen peroxide alone or urate crystals and uricase in combination (but neither alone) induced maturation of dendritic cells in human serum. In humans lacking uricase, the mitochondria of apoptotic cells produce abundant reactive oxygen species. Our results suggest that the reactive oxygen species, rather than the uric acid, may be the ultimate danger signal.
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