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

Giuseppe Maulucci, M Illario, Ml Giardino Torchia, U Sankar, Tj Ribar, M Galgani, L Vitiello, Am Masci, Fr Bertani, E Ciaglia, D Astone, A Cavallo, M Vitale, V Cimini, L Pastore, Ar Means, G Rossi, L. Racioppi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

55 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)723-731
Numero di pagine9
RivistaBlood
Volume111
DOI
Stato di pubblicazionePubblicato - 2008

Keywords

  • Calmodulin
  • Confocal microscopy

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