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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1836-1843
IMMUNOBIOLOGY
Activation of macrophage cytostatic effector mechanisms
during acute graft-versus-host disease: release of intracellular
iron and nitric oxide-mediated cytostasis
Frederick P. Nestel,
Robert
N. Greene,
Krikor Kichian,
Premysl Ponka, and
Wayne S. Lapp
From the Department of Physiology, McGill University,
Montreal, Canada; and the Lady Davis Institute for Medical Research of
the Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec,
Canada.
During acute graft-versus-host disease (GVHD) the activation of
macrophages (M ) is mediated by 2 signals, interferon (IFN)- and
bacteria-derived lipopolysaccharide (LPS). A cascade of inflammatory responses that includes the release of mediators of tissue injury follows M activation. Among the tissues characteristically targeted during acute GVHD are epithelial tissues of the skin and
gastrointestinal tract that normally undergo continuous proliferation
and are therefore sensitive to cytostatic processes. We have
investigated whether M can mediate cytostatic mechanisms capable of
interrupting cell proliferation during acute GVHD. GVHD was induced in
nonirradiated C57BL/6XAF1 (B6AF1) mice by the
injection of 60 × 106 (acute GVHD) or
30 × 106 (nonlethal GVHD) C57BL/6 (B6) lymphoid cells.
M from animals undergoing acute GVHD could be triggered by normally
insignificant quantities of LPS to mediate a cytostatic effect on
target cells, resulting in the complete shutdown of cellular
proliferation. The same amounts of LPS had no effect on M from
normal or syngeneically transplanted animals. M mediated the release
of significant quantities of intracellular iron from target cells
undergoing cytostasis. Reversal of cytostasis occurred following
inhibition of nitric oxide (NO) production by
NG-monomethyl-L-arginine (NMMA). Production of NO by
LPS-triggered M reflected the severity of GVHD. NO release increased
significantly during acute GVHD but was only transiently increased
during nonlethal GVHD. The results provide evidence that, as a result
of activation during acute GVHD, M produce NO and induce the release
of iron from target cells, resulting in a potent cytostatic effect that inhibits cellular proliferation.
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