SEARCH:   Advanced

Blood, 1 April 2007, Vol. 109, No. 7, pp. 2903-2911. Prepublished online as a Blood First Edition Paper on December 12, 2006; DOI 10.1182/blood-2006-07-033597. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-07-033597v1 109/7/2903    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 Fujisawa, A. Articles by Miyachi, Y. Search for Related Content PubMed PubMed Citation Articles by Fujisawa, A. Articles by Miyachi, Y. Related Collections Apoptosis Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Disease-associated mutations in CIAS1 induce cathepsin B–dependent rapid cell death of human THP-1 monocytic cells Akihiro Fujisawa1, Naotomo Kambe1, Megumu Saito2, Ryuta Nishikomori2, Hideaki Tanizaki1, Nobuo Kanazawa1,3, Souichi Adachi2, Toshio Heike2, Junji Sagara4, Takashi Suda5, Tatsutoshi Nakahata2, and Yoshiki Miyachi1 1 Department of Dermatology, Kyoto University Graduate School of Medicine, Japan; 2 Department of Pediatrics, Kyoto University Graduate School of Medicine, Japan; 3 Department of Dermatology, Wakayama Medical University, Japan; 4 Department of Biochemical Laboratory Science, School of Health Science, Shinshu University, Nagano, Japan; 5 Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-B regulation and caspase-1–mediated maturation of interleukin 1ß. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B–specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B–dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Saito, R. Nishikomori, N. Kambe, A. Fujisawa, H. Tanizaki, K. Takeichi, T. Imagawa, T. Iehara, H. Takada, T. Matsubayashi, et al. Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients Blood, February 15, 2008; 111(4): 2132 - 2141. [Abstract] [Full Text] [PDF] J. A. Duncan, D. T. Bergstralh, Y. Wang, S. B. Willingham, Z. Ye, A. G. Zimmermann, and J. P.-Y. Ting Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling PNAS, May 8, 2007; 104(19): 8041 - 8046. [Abstract] [Full Text] [PDF]

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020