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. 2004 Nov;9(11):1055-67.
doi: 10.1111/j.1365-2443.2004.00789.x.

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

Masatatsu Yamamoto  1 , Katsuyuki Yaginuma, Hiroko Tsutsui, Junji Sagara, Xin Guan, Ekihiro Seki, Koubun Yasuda, Masahiro Yamamoto, Shizuo Akira, Kenji Nakanishi, Tetsuo Noda, Shun'ichiro Taniguchi
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Free article

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

Masatatsu Yamamoto et al. Genes Cells. 2004 Nov.
Free article

Abstract

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-beta (Trif), to induce various pro-inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL-1beta 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-1beta 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-1beta 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-1beta/IL-18 via activation of caspase-1 and provide new insights into the inflammatory responses for host defence and diseases.

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