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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 18, 2007 Accepted September 25, 2007 Calmodulin-dependent kinase IV links toll-like receptor 4 signaling with survival pathway of activated denditric cells Maddalena Illario, Maria L Giardino-Torchia, Uma Sankar, Thomas J Ribar, Mario Galgani, Laura Vitiello, Anna Maria Masci, Francesca R Bertani, Elena Ciaglia, Dalila Astone, Giuseppe Maulucci, Anna Cavallo, Mario Vitale, Vincenzo Cimini, Lucio Pastore, Anthony R Means, Guido Rossi, and Luigi Racioppi* Department of Molecular and Cellular Biology and Pathology, "Federico II" University of Naples, Naples, Italy Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States Laboratory of Immunobiology of Cardiovascular Diseases, Dept of Medical Sciences & Rehabilitation, IRCCS San Raffaele, Rome, Italy Laboratory of Cellular & Molecular Pathology, IRCCS San Raffaele, Rome, Italy CEINGE-Advanced Biotechnology, Naples, Italy Institute of Physic, University "Sacro Cuore", Rome, Italy Dept of Endocrinology and Molecular and Clinical Oncology, "Federico II" University of Naples, Naples, Italy Department of Biomorphological and Functional Science, "Federico II" University of Naples, Naples, Italy Department of Biochemistry and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy Interdipartimental Center for Immunological Sciente (CISI), "Federico II" University of Naples, Naples, Italy * Corresponding author; email: racioppi{at}unina.it. Microbial products, including lipopolysacharide, an agonist of Toll-like receptor 4 (TLR4), regulate the lifespan of dendritic cells (DC) by largely undefined mechanisms. Here, we identify a role for calcium-calmodulin-dependent kinase IV (CaMKIV) in this survival program. The pharmacological inhibition of CaMKs as well as ectopic expression of kinase-inactive CaMKIV decreases the viability of monocyte-derived dendritic cells (DC) exposed to bacterial lipopolysacharide (LPS). The defect in TLR-4 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 DC in lymphoid tissues and fail to accumulate mature DC in spleen upon in vivo exposure to LPS. Although isolated Camk4-/- DC 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 TLR-4 and a calcium-dependent signaling cascade comprised of 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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