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*
The Wistar Institute, Philadelphia, PA 19104;
University of Pennsylvania, Veterinary School, Philadelphia, PA 19104; and
Johns Hopkins University School of Medicine, Baltimore, MD 21205
Endotoxin tolerance, the transient, secondary down-regulation of a
subset of endotoxin-driven responses after exposure to bacterial
products, is thought to be an adaptive response providing protection
from pathological hyperactivation of the innate immune system during
bacterial infection. However, although protecting from the development
of sepsis, endotoxin tolerance also can lead to fatal blunting of
immunological responses to subsequent infections in survivors of septic
shock. Despite considerable experimental effort aimed at characterizing
the molecular mechanisms responsible for a variety of endotoxin
tolerance-related phenomena, no consensus has been achieved yet. IL-12
is a macrophage- and dendritic cell (DC)-derived cytokine that plays a
key role in pathological responses to endotoxin as well as in the
induction of protective responses to pathogens. It recently has been
shown that IL-12 production is suppressed in endotoxin tolerance,
providing a likely partial mechanism for the increased risk of
secondary infections in sepsis survivors. We examined the development
of IL-12 suppression during endotoxin tolerance in mice. Decreased
IL-12 production in vivo is clearly multifactorial, involving both loss
of CD11chigh DCs as well as alterations in the
responsiveness of macrophages and remaining splenic DCs. We find no
demonstrable mechanistic role for B or T lymphocytes, the soluble
mediators IL-10, TNF-
, IFN-
, or nitric oxide, or the NF-
B
family members p50, p52, or RelB.
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