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

• Published in: Genes to cells : devoted to molecular & cellular mechanisms Vol. 9; no. 11; pp. 1055 - 1067
• Main Authors: Yamamoto, Masatatsu, Yaginuma, Katsuyuki, Tsutsui, Hiroko, Sagara, Junji, Guan, Xin, Seki, Ekihiro, Yasuda, Koubun, Yamamoto, Masahiro, Akira, Shizuo, Nakanishi, Kenji, Noda, Tetsuo, Taniguchi, Shun’ichiro
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.11.2004
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Antigens, Differentiation - physiology; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Caspase 1; Caspases - metabolism; Cytokines - secretion; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - physiology; Enzyme Activation; Enzyme Precursors - metabolism; Enzyme-Linked Immunosorbent Assay; Lipopolysaccharides - pharmacology; Membrane Glycoproteins - physiology; Mice; Mice, Knockout; Myeloid Differentiation Factor 88; Receptors, Cell Surface - physiology; Receptors, Immunologic - physiology; Toll-Like Receptor 4; Toll-Like Receptors
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/j.1365-2443.2004.00789.x

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‐β (Trif), to induce various pro‐inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL‐1β 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‐1β and pro‐IL‐18, but normally produced other pro‐inflammatory cytokines including TNF‐α 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‐1β 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‐1β/IL‐18 via activation of caspase‐1 and provide new insights into the inflammatory responses for host defence and diseases.