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Departments of 1 Anesthesia and 2 Cardiac Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
In the heart, lipopolysaccharide (LPS)
induces the production of proinflammatory cytokines that cause
myocardial dysfunction; however, the signaling pathways involved in
cardiomyocyte responses are poorly understood. We studied LPS-induced
signaling by treating cardiomyocyte cultures with 0.01-10 µg/ml
LPS for 0-24 h in the presence or absence of 2.5% serum.
Cytosolic and nuclear proteins were analyzed for expression and
activation of protein kinases. Members of the extracellular
signal-regulated kinase (ERK) and signal transducer and activators of
transcription (STAT) protein families were uniformly expressed and
specifically phosphorylated in response to LPS. Activation was
biphasic; peaking at 5-10 min and 24 h after treatment.
Inhibitor experiments provided evidence that ERK proteins may regulate
STAT activity. Serum did not augment endotoxin-induced phosphorylation.
Although cardiomyocytes expressed low levels of CD14 and LPS-binding
protein, specific enzymatic removal of glycosyl
phosphatidylinositol-linked receptors or incubation with an anti-CD14
antibody had no effect on kinase activation. Treatment of cells with an
excess of detoxified LPS attenuated endotoxin-induced signaling. In
addition, endotoxin stimulated specific binding of nuclear factors to
AP-1, nuclear factor-
B (NF-B), STAT1 (SIE, sis-inducible
element), and STAT3 consensus-binding sequences. Finally, inhibition of
ERK phosphorylation reduced, and NF-B nuclear translocation
prevented, tumor necrosis factor-
production. Our results indicate
that LPS-induced activation of signal transduction in cardiomyocytes
occurs by a CD14-independent mechanism.
lipopolysaccharide; kinase; receptor; phosphorylation; myocyte
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