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Production and Lipopolysaccharide-Induced Endotoxic Shock1
,§,
,§
*
Department of Microbiology and Immunology and the University of North Carolina Neuroscience Center;
Program for Molecular Biology and Biotechnology;
Department of Pharmacology and Lineberger Comprehensive Cancer Center; and
§
Department of Medicine, University of North Carolina, Chapel Hill, NC 27599
The regulation of monocyte function and the inhibition of TNF-
production during bacterial sepsis are critical in attenuating adverse
host responses to endotoxemia. To study the function of a novel
receptor tyrosine kinase, mer, that is expressed in
monocytes, we generated mice (merkd) that
lack the signaling tyrosine kinase domain. Upon LPS challenge,
merkd animals died of endotoxic shock
(15/17, 88.2%), whereas control wild-type mice survived (1/15, 6.7%
died). Susceptible merkd mice exhibited
edema, leukocyte infiltration, and signs of endotoxic shock that
correlated with higher levels of TNF- found in the serum of
merkd mice as compared with wild-type
control animals. Death due to LPS-induced endotoxic shock in
merkd mice was blocked by administration of
anti-TNF- Ab, suggesting that overproduction of this cytokine
was principally responsible for the heightened suseptibility. The
increase in TNF- production appeared to be the result of a
substantial increase in the LPS-dependent activation of NF-
B nuclear
translocation resulting in greater TNF- production by macrophages
from merkd mice. Thus, Mer receptor tyrosine
kinase signaling participates in a novel inhibitory pathway in
macrophages important for regulating TNF- secretion and attenuating
endotoxic shock.
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