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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.
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Submitted July 5, 2006
Accepted November 22, 2006
Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells
Akihiro Fujisawa, Naotomo Kambe*, Megumu Saito, Ryuta Nishikomori, Hideaki Tanizaki, Nobuo Kanazawa, Souichi Adachi, Toshio Heike, Junji Sagara, Takashi Suda, Tatsutoshi Nakahata, and Yoshiki Miyachi
Dept of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Dept of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Dept of Dermatology, Wakayama Medical University, Wakayama, Japan
Dept of Biochemical Laboratory Science, School of Health Science, Shinshu University, Nagano, Japan
Division of Immunology & Molecular Biology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan
* Corresponding author; email: nkambe{at}kuhp.kyoto-u.ac.jp.
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 1 . 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 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 disease associated mutation-induced 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.
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