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Blood, 15 January 2008, Vol. 111, No. 2, pp. 723-731. Prepublished online as a Blood First Edition Paper on October 1, 2007; DOI 10.1182/blood-2007-05-091173. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-05-091173v1 111/2/723    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Illario, M. Articles by Racioppi, L. Search for Related Content PubMed PubMed Citation Articles by Illario, M. Articles by Racioppi, L. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells Maddalena Illario1, Maria L. Giardino-Torchia1, Uma Sankar2, Thomas J. Ribar2, Mario Galgani1, Laura Vitiello1,3, Anna Maria Masci1,3, Francesca R. Bertani4, Elena Ciaglia1, Dalila Astone5,6, Giuseppe Maulucci7, Anna Cavallo1, Mario Vitale8, Vincenzo Cimini9, Lucio Pastore5,6, Anthony R. Means2, Guido Rossi1,10, and Luigi Racioppi1,10 1 Department of Molecular and Cellular Biology and Pathology, Federico II University of Naples, Naples, Italy; 2 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC; 3 Laboratory of Immunobiology of Cardiovascular Diseases, Department of Medical Science and Rehabilitation, and 4 Laboratory of Cellular and Molecular Pathology, Scientific Institute for Research, Hospitalization, and Health Care (IRCCS) San Raffaele Pisana, Rome, Italy; 5 Center for Genetic Engineering (CEINGE) Advanced Biotechnology, Naples, Italy; 6 Department of Biochemistry and Medical Biotechnology, Federico II University of Naples, Naples, Italy; 7 Institute of Physics, University Sacro Cuore, Rome, Italy; 8 Department of Endocrinology and Molecular and Clinical Oncology 9 Department of Biomorphological and Functional Science, and 10 Interdepartimental Center for Immunological Science, Federico II University of Naples, Naples, Italy 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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