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]

Abstract

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.

Tumor necrosis factor‐α and embryonic mouse lung morphogenesis

“…3C). This up-regulation might seem to conflict with results from several in vitro (Kutteh et al, 1991;Martinet et al, 1992) and in vivo Mier et al, 1990;Chensue et al, 1991) studies showing down-regulation of TNF-a by CORT. However, while CORT may suppress TNF-a levels in serum or in cultured cell supernatants, TNF-a mRNA and protein levels within tissues may be less susceptible to CORT regulation (Ulich et al, 1990;Jevnikar et al, 1992;Lane et al, 1993).…”

Glucocorticoids as cytokine inhibitors: role in neuroendocrine control and therapy of inflammatory diseases

“…In human volunteers giving an injection of LPS, GC inhibited IL-6 and TNF production. 4'41 DEX, administered to IL-2 treated cancer patients 42 or to patients undergoing cardiopulmonary bypass, 43 reduced the TNF production observed in these conditions.…”

Negative inotropic effects of recombinant interleukin 2 in patients without left ventricular dysfunction

“…T‐cells are an important source of IL2. IL2 itself has negative inotropic activity and it is able to stimulate production of TNFα and other cytokines [–]. Increased plasma levels of TNFα have been found in patients with advanced heart failure [].…”