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The role of hyperuricemia in the increased cytokine production after
lipopolysaccharide challenge in neutropenic mice
MG Netea, BJ Kullberg, WL Blok, RT Netea and JW van der Meer
Department of Medicine, University Hospital Nijmegen, The Netherlands.
Patients with severe granulocytopenia are more susceptible to severe
infections and sepsis. Proinflammatory cytokines such as tumor necrosis
factor-alpha (TNF), interleukin-1 alpha (IL-1 alpha), and IL-1 beta play an
important role in the pathophysiology of sepsis. The profile of these
proinflammatory cytokines after lipopolysaccharide (LPS) challenge in
cyclophosphamide-induced neutropenic mice was assessed, and possible
mechanisms responsible for the modified cytokine production were studied.
After LPS, both circulating concentrations of TNF and IL-1 alpha in
neutropenic mice were 50% to 200% higher than those of controls, whereas
IL-1 beta concentrations were not modified. The kinetics of cytokine
production were similar in neutropenic and control animals. The
susceptibility of neutropenic mice to an LPS challenge was increased. The
observed overproduction of TNF and IL-1 alpha was not due to a direct
effect of cyclophosphamide treatment. Because circulating concentrations of
uric acid were increased in the neutropenic mice, the effect of
hypouricemic treatment with allopurinol and sodium bicarbonate was
investigated; such treatment in neutropenic mice challenged with LPS was
followed by an improved survival and a reduced proinflammatory cytokine
production towards the concentrations in control mice. Hyperuricemia
induced by repeated administrations of uric acid in normal mice led to an
increased TNF production after LPS. In conclusion, neutropenic mice respond
with enhanced cytokine production and increased susceptibility to an LPS
challenge, and hyperuricemia probably plays an important role in this
phenomenon.
Volume 89,
Issue 2,
pp. 577-582,
01/15/1997
Copyright © 1997 by The American Society of Hematology
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