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/IL-18 Secretion in Response to Listeria monocytogenes1
lkim Ertürk*


* Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109; and
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139
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
/IL-18, but dispensable for IL-6, TNF-
, and IFN-
production, in macrophages infected with Listeria. Activation of caspase-1 was abolished in ASC-deficient macrophages, whereas activation of NF-
B and p38 was unaffected. In contrast, secretion of IL-1
, IL-6, and TNF-
was reduced in TLR2-deficient macrophages infected with Listeria; this was associated with impaired activation of NF-
B and p38, but normal caspase-1 processing. Analysis of Listeria mutants revealed that cytosolic invasion was required for ASC-dependent IL-1
secretion, consistent with a critical role for cytosolic signaling in the activation of caspase-1. Secretion of IL-1
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
via distinct mechanisms in response to Listeria. ASC, but not TLR2, is required for caspase-1 activation independent of NF-
B in Listeria-infected macrophages.
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