Abstract
Macrophage activation by bacterial lipopolysaccharide (LPS) promotes the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and of secondary mediators, such as leukotrienes and prostaglandins (PGs). Mice lacking the gene encoding the serine/threonine protein kinase Tpl2/Cot produce low levels of TNF-alpha in response to LPS because of an ERK-dependent post-transcriptional defect, and they are resistant to LPS/D-galactosamine-induced endotoxin shock. In this study we demonstrate that prostaglandin E2 and its regulatory enzyme, COX-2, are also targets of Tpl2-transduced LPS signals in bone marrow-derived mouse macrophages. Thus, LPS-stimulated Tpl2(-/-) macrophages express low levels of COX-2 and PGE2, compared with wild-type Tpl2(+/+) cells. The ability of Tpl2 to regulate COX-2 expression depends on ERK signals that activate p90Rsk and Msk1, which in turn phosphorylate CREB, a key regulator of COX-2 transcription. These data identify physiological targets of Tpl2 signaling downstream of ERK and further implicate Tpl2 in the pathophysiology of inflammation.
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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Animals
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Cell Line
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Cyclooxygenase 2
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Dinoprostone / metabolism
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Enzyme Induction
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Genes, Reporter
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Glycogen Synthase Kinase 3 / metabolism
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Inflammation / metabolism
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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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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Macrophage Activation / physiology*
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Macrophages / drug effects*
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Macrophages / metabolism
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Mice
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Peroxidases / metabolism
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Plant Proteins / metabolism
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Promoter Regions, Genetic
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Stability
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
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Signal Transduction / physiology*
Substances
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Cyclic AMP Response Element-Binding Protein
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Isoenzymes
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Lipopolysaccharides
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Plant Proteins
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Proto-Oncogene Proteins
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Peroxidases
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Ribosomal Protein S6 Kinases, 90-kDa
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MAP Kinase Kinase Kinases
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Map3k8 protein, mouse
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Glycogen Synthase Kinase 3
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Msk-1 protein, Medicago sativa
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Dinoprostone