Ozören Nesrin, Masumoto Junya, Franchi Luigi, Kanneganti Thirumala-Devi, Body-Malapel Mathilde, Ertürk Ilkim, Jagirdar Rajesh, Zhu Li, Inohara Naohiro, Bertin John, Coyle Anthony, Grant Ethan P, Núñez Gabriel
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, USA.
J Immunol. 2006 Apr 1;176(7):4337-42. doi: 10.4049/jimmunol.176.7.4337.
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.
含C端半胱天冬酶募集结构域的凋亡相关斑点样蛋白（ASC）是一种衔接分子，最近被认为与半胱天冬酶-1的激活有关。我们研究了ASC在宿主抵御细胞内病原体单核细胞增生李斯特菌中的作用。结果发现，在感染李斯特菌的巨噬细胞中，ASC对于IL-1β/IL-18的分泌至关重要，但对于IL-6、TNF-α和IFN-β的产生则是可有可无的。在ASC缺陷型巨噬细胞中，半胱天冬酶-1的激活被消除，而NF-κB和p38的激活不受影响。相反，在感染李斯特菌的TLR2缺陷型巨噬细胞中，IL-1β、IL-6和TNF-α的分泌减少；这与NF-κB和p38的激活受损有关，但半胱天冬酶-1的加工正常。对李斯特菌突变体的分析表明，ASC依赖的IL-1β分泌需要胞质入侵，这与胞质信号在半胱天冬酶-1激活中的关键作用一致。在ASC缺失的巨噬细胞中，对TLR2激动剂脂肽的反应中IL-1β的分泌大大减少，而在TLR2缺陷型巨噬细胞中则被消除。这些结果表明，TLR2和ASC通过不同机制调节对李斯特菌反应时IL-1β的分泌。在感染李斯特菌的巨噬细胞中，ASC而非TLR2是半胱天冬酶-1独立于NF-κB激活所必需的。
