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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / physiology
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Caspase 1
  • Caspases / metabolism*
  • Cytokines / metabolism
  • 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

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Cytokines
  • Cytoskeletal Proteins
  • Enzyme Precursors
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Pycard protein, mouse
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Caspases
  • Caspase 1