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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-
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.
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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