Abstract
Tpl2 knockout mice produce low levels of TNF-alpha when exposed to lipopolysaccharide (LPS) and they are resistant to LPS/D-Galactosamine-induced pathology. LPS stimulation of peritoneal macrophages from these mice did not activate MEK1, ERK1, and ERK2 but did activate JNK, p38 MAPK, and NF-kappaB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-alpha induction by experiments showing that normal murine macrophages treated with the MEK inhibitor PD98059 exhibit a similar defect. Deletion of the AU-rich motif in the TNF-alpha mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-alpha. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport of TNF-alpha mRNA from the nucleus to the cytoplasm.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3' Untranslated Regions / physiology
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / immunology
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Animals
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Bone Marrow Cells / immunology
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Cytoplasm / metabolism
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Female
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Galactosamine / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology*
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Lipopolysaccharides / pharmacology*
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / immunology*
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Macrophages, Peritoneal / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 7
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Processing, Post-Transcriptional / drug effects
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RNA Processing, Post-Transcriptional / immunology*
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RNA, Messenger / metabolism
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Shock, Septic / chemically induced
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Shock, Septic / physiopathology
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Spleen / cytology
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Spleen / immunology
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Thioglycolates / pharmacology
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Tumor Necrosis Factor-alpha / genetics*
Substances
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3' Untranslated Regions
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Lipopolysaccharides
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NF-kappa B
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Proto-Oncogene Proteins
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RNA, Messenger
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Thioglycolates
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Tumor Necrosis Factor-alpha
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Galactosamine
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 7
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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Map3k8 protein, mouse