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Modulating activity of interferon-gamma on endotoxin-induced cytokine
production in cancer patients
A Mackensen, C Galanos and R Engelhardt
Medizinische Klinik I der Albert-Ludwigs-Universitat, Freiburg, Germany.
Intravenous (IV) administration of purified lipopolysaccharide (LPS) from
Salmonella abortus equi to cancer patients induces the formation of high
amounts of endogenous cytokines such as tumor necrosis factor- alpha
(TNF-alpha) and interleukin-6 (IL-6). On repeated administration of LPS at
2-week intervals, a marked downregulation of the cytokine response was
observed, especially between the first and the second challenge. This study
sought to determine whether it would be possible to prevent this
downregulation by pretreating patients with interferon- gamma (IFN-gamma),
which is known to enhance cytokine production by monocytes and macrophages
in vitro. Ten patients with disseminated cancer received a first injection
of 4.0 ng LPS/kg. Thereafter, patients were divided into two groups. One
group received two further LPS injections (4.0 ng/kg) at 2-week intervals.
The second group was pretreated (-12 hours) with 50 micrograms IFN-gamma
subcutaneously (SC) before the second and third LPS challenge. To prevent
constitutional side effects such as fever and chills, patients received
1,600 mg ibuprofen orally before LPS injection. The results of the current
study demonstrate that apart from TNF-alpha and IL-6, two other cytokines,
interleukin-8 (IL-8) and granulocyte colony-stimulating factor (G-CSF) are
produced in cancer patients in response to LPS. LPS application at 2-week
intervals resulted in a transient attenuation of all cytokines (TNF-alpha,
IL-6, IL-8, G-CSF) on the second challenge. In the case of TNF-alpha, IL-6,
and G-CSF, pretreatment with IFN-gamma not only prevented the
downregulation, but enhanced the production of these cytokines to levels
higher than those obtained after the first LPS challenge. In contrast, the
downregulation of IL-8 remained unaffected by IFN-gamma pretreatment.
Further studies are warranted to determine whether the prevention of
cytokine downregulation by IFN-gamma following repeated LPS injections is
of clinical relevance in respect to the antitumor activity of LPS.
Volume 78,
Issue 12,
pp. 3254-3258,
12/15/1991
Copyright © 1991 by The American Society of Hematology
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