The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice.
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.
Netea
M G
MG
Department of Medicine, University Hospital Nijmegen, The Netherlands.
Kullberg
B J
BJ
Blok
W L
WL
Netea
R T
RT
van der Meer
J W
JW
D000380:Agranulocytosis / Q000097:blood* / Q000139:chemically induced; D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity*; D005260:Female; D007375:Interleukin-1 / Q000097:blood*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid; D003520:Cyclophosphamide