title: Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells.
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.
authors.affiliation: Department of Molecular and Cellular Biology and Pathology, Federico II University of Naples, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Illario
authors.forename: Maria L
authors.initials: ML
authors.lastname: Giardino-Torchia
authors.forename: Uma
authors.initials: U
authors.lastname: Sankar
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ribar
authors.forename: Mario
authors.initials: M
authors.lastname: Galgani
authors.forename: Laura
authors.initials: L
authors.lastname: Vitiello
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Masci
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Bertani
authors.forename: Elena
authors.initials: E
authors.lastname: Ciaglia
authors.forename: Dalila
authors.initials: D
authors.lastname: Astone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maulucci
authors.forename: Anna
authors.initials: A
authors.lastname: Cavallo
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cimini
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Means
authors.forename: Guido
authors.initials: G
authors.lastname: Rossi
authors.forename: Luigi
authors.initials: L
authors.lastname: Racioppi
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse