Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells.
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.
Illario
Maddalena
M
Department of Molecular and Cellular Biology and Pathology, Federico II University of Naples, Italy.
Giardino-Torchia
Maria L
ML
Sankar
Uma
U
Ribar
Thomas J
TJ
Galgani
Mario
M
Vitiello
Laura
L
Masci
Anna Maria
AM
Bertani
Francesca R
FR
Ciaglia
Elena
E
Astone
Dalila
D
Maulucci
Giuseppe
G
Cavallo
Anna
A
Vitale
Mario
M
Cimini
Vincenzo
V
Pastore
Lucio
L
Means
Anthony R
AR
Rossi
Guido
G
Racioppi
Luigi
L
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
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