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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1618-1626. Prepublished online as a Blood First Edition Paper on May 9, 2006; DOI 10.1182/blood-2006-03-014126. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-03-014126v1 108/5/1618    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Carta, S. Articles by Rubartelli, A. Search for Related Content PubMed PubMed Citation Articles by Carta, S. Articles by Rubartelli, A. Related Collections Immunobiology Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Histone deacetylase inhibitors prevent exocytosis of interleukin-1-containing secretory lysosomes: role of microtubules Sonia Carta, Sara Tassi, Claudia Semino, Gianluca Fossati, Paolo Mascagni, Charles A. Dinarello, and Anna Rubartelli From the Laboratory of Experimental Oncology E, National Cancer Research Institute, Genoa, Italy; the Center for Research, Italfarmaco, Cinisello Balsamo, Milan, Italy; and the Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver. A number of agents reducing interleukin-1 (IL-1) activity are being developed as novel immunomodulatory and anti-inflammatory therapies. However, the elucidation of their molecular mechanism of action is required in the context of medical management of inflammatory diseases. Inhibitors of histone deacetylases (HDACs) are promising anticancer agents with pleiotropic activities. Of these, suberoylanilide hydroxamic acid has been reported to inhibit the production of several proinflammatory cytokines. In the present study, we investigated the effects of 2 HDAC inhibitors on IL-1 secretion: suberoylanilide hydroxamic acid and a newly developed hydroxamic acid-derived compound ITF2357. These HDAC inhibitors do not affect the synthesis or intracellular localization of IL-1 but both strongly reduce the levels of extracellular IL-1 by preventing the exocytosis of IL-1-containing secretory lysosomes. At nanomolar concentrations, ITF2357 reduces the secretion of IL-1 following ATP activation of the P2X7 receptor. Whereas the inhibition of HDACs results in hyperacetylation of tubulin, acetylation of HSP90 was unaffected. The reduction in IL-1 secretion appears to be due to disruption of microtubules impairing lysosome exocytosis. Together, these observations indicate that a functional microtubule network is required for IL-1 secretion and suggest that disruption of tubulin is the mechanism by which inhibitors of HDACs reduce the secretion of IL-1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. R. Silverman, J. P. de Rivero Vaccari, S. Locovei, F. Qiu, S. K. Carlsson, E. Scemes, R. W. Keane, and G. Dahl The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes J. Biol. Chem., July 3, 2009; 284(27): 18143 - 18151. [Abstract] [Full Text] [PDF] R. Hazama, X. Qu, K. Yokoyama, C. Tanaka, E. Kinoshita, J. He, S. Takahashi, K. Tohyama, H. Yamamura, and Y. Tohyama ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk Genes Cells, July 1, 2009; 14(7): 871 - 884. [Abstract] [Full Text] [PDF] T. Takenouchi, M. Nakai, Y. Iwamaru, S. Sugama, M. Tsukimoto, M. Fujita, J. Wei, A. Sekigawa, M. Sato, S. Kojima, et al. The Activation of P2X7 Receptor Impairs Lysosomal Functions and Stimulates the Release of Autophagolysosomes in Microglial Cells J. Immunol., February 15, 2009; 182(4): 2051 - 2062. [Abstract] [Full Text] [PDF] A. Piccini, S. Carta, S. Tassi, D. Lasiglie, G. Fossati, and A. Rubartelli ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1{beta} and IL-18 secretion in an autocrine way PNAS, June 10, 2008; 105(23): 8067 - 8072. [Abstract] [Full Text] [PDF] Y. Qu, L. Franchi, G. Nunez, and G. R. Dubyak Nonclassical IL-1beta Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages J. Immunol., August 1, 2007; 179(3): 1913 - 1925. [Abstract] [Full Text] [PDF] M. Baroni, C. Pizzirani, M. Pinotti, D. Ferrari, E. Adinolfi, S. Calzavarini, P. Caruso, F. Bernardi, and F. Di Virgilio Stimulation of P2 (P2X7) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles FASEB J, June 1, 2007; 21(8): 1926 - 1933. [Abstract] [Full Text] [PDF]

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