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B Activity Underlies the Pro- and Anti-Inflammatory Actions of Nitric Oxide1
Wolfson Institute for Biomedical Research, University College London, London, United Kingdom
Expression of inducible NO synthase (iNOS) by macrophages is a
prerequisite for the production of high output NO, which mediates many
bactericidal and tumoricidal actions of these immune cells. The
expression of iNOS in mammalian cells is governed predominantly by the
transcription factor, NF-
B, which regulates the expression of many
host defense proteins. In the present study, we characterize a novel,
biphasic effect of NO on NF-B activity in murine macrophages. This
mechanism depends on the local concentration of NO and enables it both
to up- and down-regulate the expression of host defense proteins
including iNOS, cyclooxygenase-2, and IL-6. This biphasic activity of
NO appears to play a pivotal role in the time course of activation of
these immune cells and, by inference, in facilitating the initiation of
a defense response against pathogenic stimuli and in its termination to
limit tissue damage. This mechanism may explain at least in part the
reported ability of NO to act in both a pro- and anti-inflammatory
manner.
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