Journal
JOURNAL OF IMMUNOLOGY
Volume 176, Issue 7, Pages 4337-4342Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.7.4337
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- NIAID NIH HHS [AI064748, AI063331] Funding Source: Medline
- NIGMS NIH HHS [GM60421] Funding Source: Medline
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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-1 beta/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-kappa B and p38 was unaffected. In contrast, secretion of IL-1 beta, IL-6, and TNF-a was reduced in TLR2-deficient macrophages infected with Listeria; this was associated with impaired activation of NF-kappa B and p38, but normal caspase-1 processing. Analysis of Listeria mutants revealed that cytosolic invasion was required for ASC-dependent IL-10 secretion, consistent with a critical role for cytosolic signaling in the activation of caspase-1. Secretion of IL-1 beta; 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-1 beta via distinct mechanisms in response to Listeria. ASC, but not TLR2, is required for caspase-1 activation independent of NF-kappa B in Listeria-infected macrophages.
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