Distinct roles of TLR2 and the adaptor ASC in IL-1beta/IL-18 secretion in response to Listeria monocytogenes.
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.
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, USA.
Nesrin
N
Ozören
Junya
J
Masumoto
Luigi
L
Franchi
Thirumala-Devi
TD
Kanneganti
Mathilde
M
Body-Malapel
Ilkim
I
Ertürk
Rajesh
R
Jagirdar
Li
L
Zhu
Naohiro
N
Inohara
John
J
Bertin
Anthony
A
Coyle
Ethan P
EP
Grant
Gabriel
G
Núñez
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D016899:Interferon-beta / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008074:Lipoproteins / Q000494:pharmacology; D008089:Listeria monocytogenes / Q000276:immunology* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D008074:Lipoproteins; C498534:Pycard protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D020170:Caspase 1