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Inhibition of the defense system stimulating interleukin-12 interferon-
gamma pathway during critical Illness
W Ertel, M Keel, R Neidhardt, U Steckholzer, JP Kremer, U Ungethuem and O Trentz
Division of Trauma Surgery, University Hospital Zurich, Switzerland.
Interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) exert protective
effects during experimental endotoxemia through upregulation of cellular
immunity and phagocytic functions. They are part of a positive regulatory
feedback loop that enhances the production of the other. Because critically
ill patients show a marked suppression of T- cell and macrophage functions
with a high susceptibility to infection, potential defects in the
immunity/inflammation upregulating IL-12 IFN- gamma pathway were studied.
As an ex vivo model of endotoxemia, lipopolysaccharide (LPS) stimulated
whole blood from 25 critically ill patients and 12 healthy individuals was
incubated with either recombinant human (rh) IL-12 or rhIFN-gamma,
respectively. IFN-gamma dose-dependently (P < .05) increased the release
of IL-12 p40 and p70 into LPS-stimulated whole blood from healthy humans
without effect in whole blood from critically ill patients. RhIL-12 p70
enhanced (P < .05) the secretion of IFN-gamma in controls, while it was
ineffective in LPS-stimulated whole blood from critically ill patients. The
observed inhibition of the IL-12 IFN-gamma pathway is not specific to LPS,
since Staphylococcus aureus Cowan strain I (SAC)-stimulated whole blood
from critically ill patients showed similar suppression. The secretion of
IL-12 and IFN-gamma was less reduced in critically ill patients when using
isolated cultures of adherent cells or lymphocytes. Although preculture of
whole blood from healthy humans with IL-10, but not with IL-4, mimicked
suppression of the IL-12 IFN-gamma pathway similar to that observed during
critical illness, the release of antiinflammatory reacting cytokines (IL-4,
IL-10, transforming growth factor [TGF]-beta 1) was decreased into
LPS-stimulated whole blood from critically ill patients. These results
indicate at least two mechanisms responsible for dramatic disturbances of
the IL-12 IFN-gamma pathway during critical illness: (1) deactivation of
IL-12 and IFN-gamma producing leukocytes in vivo early after the primary
insult, and (2) presence of serum suppressive factors different from IL-4,
IL-10, or TGF-beta 1. Because IL-12 and IFN-gamma upregulate essential
immune functions, the marked inhibition of IL-12 and IFN-gamma release may
be pivotal for high susceptibility of critically ill patients to infection.
Volume 89,
Issue 5,
pp. 1612-1620,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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