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ASC is essential for LPS‐induced activation of procaspase‐1 independently of TLR‐associated signal adaptor molecules
Author(s) -
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
Publication year - 2004
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2004.00789.x
Subject(s) - trif , signal transducing adaptor protein , tlr4 , lipopolysaccharide , biology , microbiology and biotechnology , signal transduction , toll like receptor , tlr2 , receptor , immunology , innate immune system , immune system , biochemistry
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.