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Genes to Cells (2004) 9, 1055-1067. doi:10.1111/j.1365-2443.2004.00789.x
© 2004 Blackwell Publishing or its licensors

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ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules

Masatatsu Yamamoto1,2, Katsuyuki Yaginuma2, Hiroko Tsutsui3,4, Junji Sagara1, Xin Guan1, Ekihiro Seki3,4, Koubun Yasuda3,4, Masahiro Yamamoto5, Shizuo Akira5, Kenji Nakanishi3,4, Tetsuo Noda2,6,7,a and Shun’ichiro Taniguchi1,*

1 Department of Molecular Oncology Division of Molecular and Cellular Biology Institute on Ageing and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
2 Department of Cell Biology, Cancer Research Institute of the Japanese Foundation of Cancer Research, 1-37-1 Kamiikebukuro, Toshima-ku, Tokyo 170-8455, Japan
3 Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya 663-8501, Japan
4 Core Research of Evolutional Science and Technology, Japan Science and Technology agency, 4-1-8 Motomati, Kawaguchi 332-0012, Japan
5 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan
6 Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-cho, Aoba-Ku, Sendai 980-8575, Japan
7 Mouse Functional Genomics Research Group, Institute of Physical and Chemical Research (Japan) (RIKEN) Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa 244-0804, Japan

Toll-like receptors (TLRs) initiate a signalling cascade via association with an adaptor molecule, myeloid differentiation factor 88 (MyD88) and/or TIR domain-containing adaptor inducing-IFN-ß (Trif), to induce various pro-inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL-1ß and IL-18 are processed, depending on the activation of caspase-1, although its mechanism remains unclear. ASC is an adapter protein possibly involved in the activation of procaspase-1. To unravel the requirement of ASC, we generated Asc–/– mice. Upon stimulation with LPS, Asc–/– macrophages failed in the processing of procaspase-1 and maturation of pro-IL-1ß and pro-IL-18, but normally produced other pro-inflammatory cytokines including TNF-{alpha} and IL-6. MyD88–/– and Trif–/– macrophages showed normal activation of caspase-1, demonstrating a dispensable role for MyD88 and Trif. After, LPS-challenged Asc–/– mice lacked serum elevation of IL-1ß and IL-18. Moreover, the Asc–/– mice exhibited neither acute liver injury nor lethal shock. These results demonstrate critical roles for ASC in the release of IL-1ß/IL-18 via activation of caspase-1 and provide new insights into the inflammatory responses for host defence and diseases.


Communicated by: Shinichi Aizawa

a Requests for mice: E-mail: tnoda{at}ims.u-tokyo.ac.jp

* Correspondence: E-mail: stangch{at}sch.md.shinshu-u.ac.jp




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