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enhances cardiac myocyte NO production through MAP
kinase-mediated NF-
B
activation
Departments of 1 Medicine and
2 Pharmacology,
We have
previously reported that interleukin-1
(IL-1
) alone induced
nitric oxide (NO) production by neonatal rat cardiac myocytes (CM). The
effects of tumor necrosis factor-
(TNF-
) on inducible NO synthase
(iNOS) were not characterized. Unlike IL-1
, TNF-
alone failed to
enhance NO production in CM. However, the addition of TNF-
to
IL-1
significantly enhanced iNOS mRNA expression, iNOS protein
synthesis, and NO production (NO
2). TNF-
enhancement of IL-1
-induced
NO
2 production was blocked by
PD-98059, a selective mitogen-activated protein (MAP) kinase kinase
inhibitor, but not calphostin C (Cal C), a protein kinase C inhibitor.
TNF-
-enhanced MAP kinase activity was associated with an increase in
IL-1
-stimulated NF-
B activity. PD-98059, but not Cal C, inhibited
both TNF-
-enhanced MAP kinase and NF-
B activities. Thus TNF-
enhancement of IL-1
-induced NO production is associated with MAP
kinase-mediated activation of NF-
B.
cytokines; heart; cell signaling; tumor necrosis factor; nitric oxide; mitogen-activated protein kinase
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