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Department of Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242
This study uses human alveolar macrophages to determine whether
activation of a phosphatidylcholine (PC)-specific phospholipase C
(PC-PLC) is linked to activation of the p42/44 (ERK) kinases by LPS.
LPS-induced ERK kinase activation was inhibited by tricyclodecan-9-yl
xanthogenate (D609), a relatively specific inhibitor of PC-PLC. LPS
also increased amounts of diacylglycerol (DAG), and this increase in
DAG was inhibited by D609. LPS induction of DAG was, at least in part,
derived from PC hydrolysis. Ceramide was also increased in LPS-treated
alveolar macrophages, and this increase in ceramide was inhibited by
D609. Addition of exogenous C2 ceramide or
bacterial-derived sphingomyelinase to alveolar macrophages increased
ERK kinase activity. LPS also activated PKC 
, and this activation
was inhibited by D609. LPS-activated PKC phosphorylated MAP kinase
kinase, the kinase directly upstream of the ERK kinases. LPS-induced
cytokine production (RNA and protein) was also inhibited by D609. As an
aggregate, these studies support the hypothesis that one way by which
LPS activates the ERK kinases is via activation of PC-PLC and that
activation of a PC-PLC is an important component of macrophage
activation by LPS.
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M. M. Monick, J. M. Staber, K. W. Thomas, and G. W. Hunninghake Respiratory Syncytial Virus Infection Results in Activation of Multiple Protein Kinase C Isoforms Leading to Activation of Mitogen-Activated Protein Kinase J. Immunol., February 15, 2001; 166(4): 2681 - 2687. [Abstract] [Full Text] [PDF]
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K. M. Krishna Rao MAP kinase activation in macrophages J. Leukoc. Biol., January 1, 2001; 69(1): 3 - 10. [Abstract] [Full Text]
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M. M. Monick, A. B. Carter, D. M. Flaherty, M. W. Peterson, and G. W. Hunninghake Protein Kinase C {zeta} Plays a Central Role in Activation of the p42/44 Mitogen-Activated Protein Kinase by Endotoxin in Alveolar Macrophages J. Immunol., October 15, 2000; 165(8): 4632 - 4639. [Abstract] [Full Text] [PDF]
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K. C. Corbit, J.-W. Soh, K. Yoshida, E. M. Eves, I. B. Weinstein, and M. R. Rosner Different Protein Kinase C Isoforms Determine Growth Factor Specificity in Neuronal Cells Mol. Cell. Biol., August 1, 2000; 20(15): 5392 - 5403. [Abstract] [Full Text]
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A. B. Carter, K. L. Knudtson, M. M. Monick, and G. W. Hunninghake The p38 Mitogen-activated Protein Kinase Is Required for NF-kappa B-dependent Gene Expression. THE ROLE OF TATA-BINDING PROTEIN (TBP) J. Biol. Chem., October 22, 1999; 274(43): 30858 - 30863. [Abstract] [Full Text] [PDF]
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A. B. Carter and G. W. Hunninghake A Constitutive Active MEK right-arrow ERK Pathway Negatively Regulates NF-kappa B-dependent Gene Expression by Modulating TATA-binding Protein Phosphorylation J. Biol. Chem., September 1, 2000; 275(36): 27858 - 27864. [Abstract] [Full Text] [PDF]
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A. B. Carter, L. A. Tephly, and G. W. Hunninghake The Absence of Activator Protein 1-dependent Gene Expression in THP-1 Macrophages Stimulated with Phorbol Esters Is Due to Lack of p38 Mitogen-activated Protein Kinase Activation J. Biol. Chem., August 31, 2001; 276(36): 33826 - 33832. [Abstract] [Full Text] [PDF]
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