Abstract
Microbial products, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4), regulate the lifespan of dendritic cells (DCs) by largely undefined mechanisms. Here, we identify a role for calcium-calmodulin-dependent kinase IV (CaMKIV) in this survival program. The pharmacologic inhibition of CaMKs as well as ectopic expression of kinase-inactive CaMKIV decrease the viability of monocyte-derived DCs exposed to bacterial LPS. The defect in TLR4 signaling includes a failure to accumulate the phosphorylated form of the cAMP response element-binding protein (pCREB), Bcl-2, and Bcl-xL. CaMKIV null mice have a decreased number of DCs in lymphoid tissues and fail to accumulate mature DCs in spleen on in vivo exposure to LPS. Although isolated Camk4-/- DCs are able to acquire the phenotype typical of mature cells and release normal amounts of cytokines in response to LPS, they fail to accumulate pCREB, Bcl-2, and Bcl-xL and therefore do not survive. The transgenic expression of Bcl-2 in CaMKIV null mice results in full recovery of DC survival in response to LPS. These results reveal a novel link between TLR4 and a calcium-dependent signaling cascade comprising CaMKIV-CREB-Bcl-2 that is essential for DC survival.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CREB-Binding Protein / genetics
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CREB-Binding Protein / immunology
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CREB-Binding Protein / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 4 / immunology*
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Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism*
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / immunology
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / immunology
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dendritic Cells / cytology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism*
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Humans
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Lipopolysaccharides / immunology
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Lipopolysaccharides / metabolism
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Knockout
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Monocytes / cytology
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Monocytes / immunology
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Monocytes / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism*
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bcl-X Protein / genetics
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bcl-X Protein / immunology
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bcl-X Protein / metabolism
Substances
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Lipopolysaccharides
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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TLR4 protein, human
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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bcl-X Protein
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Bcl2 protein, mouse
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CREB-Binding Protein
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Crebbp protein, mouse
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CAMK4 protein, human
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Camk4 protein, mouse