Distinct Roles of TLR2 and the Adaptor ASC in IL-1beta/IL-18 Secretion in Response to Listeria monocytogenes

• Published in: The Journal of immunology (1950) 2006-04, Vol.176 (7), p.4337-4342
• Main Authors: Ozoren, Nesrin, Masumoto, Junya, Franchi, Luigi, Kanneganti, Thirumala-Devi, Body-Malapel, Mathilde, Erturk, Ilkim, Jagirdar, Rajesh, Zhu, Li, Inohara, Naohiro, Bertin, John, Coyle, Anthony, Grant, Ethan P, Nunez, Gabriel
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Caspase 1 - metabolism; Cells, Cultured; Cytoskeletal Proteins - deficiency; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Cytosol - metabolism; Enzyme Activation; Immunology; Interferon-beta - metabolism; Interleukin-1 - metabolism; Interleukin-18 - metabolism; Interleukin-6 - metabolism; Life Sciences; Lipoproteins - pharmacology; Listeria monocytogenes - immunology; Listeria monocytogenes - physiology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Knockout; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606

Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is an adaptor molecule that has recently been implicated in the activation of caspase-1. We have studied the role of ASC in the host defense against the intracellular pathogen Listeria monocytogenes. ASC was found to be essential for the secretion of IL-1beta/IL-18, but dispensable for IL-6, TNF-alpha, and IFN-beta production, in macrophages infected with Listeria. Activation of caspase-1 was abolished in ASC-deficient macrophages, whereas activation of NF-kappaB and p38 was unaffected. In contrast, secretion of IL-1beta, IL-6, and TNF-alpha was reduced in TLR2-deficient macrophages infected with Listeria; this was associated with impaired activation of NF-kappaB and p38, but normal caspase-1 processing. Analysis of Listeria mutants revealed that cytosolic invasion was required for ASC-dependent IL-1beta secretion, consistent with a critical role for cytosolic signaling in the activation of caspase-1. Secretion of IL-1beta in response to lipopeptide, a TLR2 agonist, was greatly reduced in ASC-null macrophages and was abolished in TLR2-deficient macrophages. These results demonstrate that TLR2 and ASC regulate the secretion of IL-1beta via distinct mechanisms in response to Listeria. ASC, but not TLR2, is required for caspase-1 activation independent of NF-kappaB in Listeria-infected macrophages.