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.

Calmodulin-dependent kinase IV links toll-like receptor 4 signaling with survival pathway of activated denditric cells / Illario, Maddalena; GIARDINO TORCHIA, M. L.; Sankar, U.; Ribar, T. J.; Galgani, Mario; Vitiello, Laura; Masci, A. M.; Bertani, F. R.; Ciaglia, Elena; Astone, D.; Maulucci, G.; Cavallo, A.; Vitale, Mario; Cimini, Vincenzo; Pastore, Lucio; Means, A. R.; Rossi, Guido; Racioppi, Luigi. - In: BLOOD. - ISSN 0006-4971. - 111:2(2008), pp. 723-731. [10.1182/blood-2007-05-091173]

Calmodulin-dependent kinase IV links toll-like receptor 4 signaling with survival pathway of activated denditric cells

ILLARIO, MADDALENA;GALGANI, MARIO;VITIELLO, Laura;CIAGLIA, ELENA;VITALE, MARIO;CIMINI, VINCENZO;PASTORE, LUCIO;ROSSI, GUIDO;RACIOPPI, LUIGI
2008

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.
2008
Calmodulin-dependent kinase IV links toll-like receptor 4 signaling with survival pathway of activated denditric cells / Illario, Maddalena; GIARDINO TORCHIA, M. L.; Sankar, U.; Ribar, T. J.; Galgani, Mario; Vitiello, Laura; Masci, A. M.; Bertani, F. R.; Ciaglia, Elena; Astone, D.; Maulucci, G.; Cavallo, A.; Vitale, Mario; Cimini, Vincenzo; Pastore, Lucio; Means, A. R.; Rossi, Guido; Racioppi, Luigi. - In: BLOOD. - ISSN 0006-4971. - 111:2(2008), pp. 723-731. [10.1182/blood-2007-05-091173]
File in questo prodotto:
File Dimensione Formato  
Blood-2008-Illario-723-31.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: Accesso privato/ristretto
Dimensione 909.16 kB
Formato Adobe PDF
909.16 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/204315
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 62
  • ???jsp.display-item.citation.isi??? 61
social impact