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Inhibition of interleukin-2-induced tumor necrosis factor release by
dexamethasone: prevention of an acquired neutrophil chemotaxis defect and
differential suppression of interleukin-2-associated side effects [see
comments]
JW Mier, G Vachino, MS Klempner, FR Aronson, R Noring, S Smith, EP Brandon, W Laird and MB Atkins
Division of Hematology-Oncology, New England Medical Center, Boston, MA
02111.
High concentrations of tumor necrosis factor (TNF) alpha have been detected
in the plasma of patients undergoing immunotherapy with interleukin 2
(IL-2), suggesting that this cytokine may play a role in the fever and
shocklike state induced by the administration of high- dose IL-2.
Dexamethasone has been shown to inhibit the synthesis of TNF by monocytes
activated in vitro by endotoxin. To determine if dexamethasone can exert a
similar suppressive effect on IL-2-induced TNF synthesis in vivo, the
concentration of TNF alpha was measured in plasma samples serially obtained
(a) from cancer patients participating in a phase I dose escalation
clinical trial with high-dose IL-2 administered in conjunction with
dexamethasone (IL-2/Dex) and (b) from patients participating in concurrent
studies with IL-2 alone. In contrast to the high plasma levels of TNF alpha
detected in patients receiving IL-2 alone, TNF levels in most of the
IL-2/Dex patients remained below the threshold of detectability of our TNF
radioimmunoassay. The concurrent administration of dexamethasone also
prevented the IL-2-induced increase in serum levels of C-reactive protein,
a hepatic acute phase reactant whose synthesis is regulated by
proinflammatory cytokines such as TNF. The steroid-treated patients also
failed to develop the neutrophil chemotactic defect characteristic of IL-2
recipients. The concomitant administration of dexamethasone increased the
maximum tolerated dose of IL-2 approximately threefold and markedly reduced
the hypotension and organ dysfunction ordinarily observed in these
patients. These results demonstrate that dexamethasone inhibits the release
of TNF into the circulation of patients undergoing immunotherapy with IL-2.
They further suggest that the altered spectrum and reduced severity of IL-2
side effects observed in patients receiving dexamethasone may be
attributable in part to the suppressive effect of steroids on IL-2-induced
TNF synthesis.
Volume 76,
Issue 10,
pp. 1933-1940,
11/15/1990
Copyright © 1990 by The American Society of Hematology
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