TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-β and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-κB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.
Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC).Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin ؊/؊ mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin ؊/؊ mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin ؊/؊ LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin ؊/؊ mice were not impaired in their capacity to process native OVA protein for I- Dendritic cells (DC) are the most potent leukocytes to mediate the rapid initiation of a primary immune response (7). DC are bone marrow-derived leukocytes, localized in most tissues including primary and secondary lymphoid organs. In the periphery, most DC are in an immature state and are able to capture antigenic molecules via unique endocytic receptors or by fluid-phase macropinocytosis. This process generally leads to a first step of DC maturation, concomitant with their migration to secondary lymphoid organs. DC can subsequently activate naive CD4 ϩ T or CD8 ϩ T lymphocytes if peptides processed from native antigenic molecules are displayed on cell surface major histocompatibility complex (MHC) class II or I molecules in conjunction with cosignaling molecules (40).DC heterogeneity is a common feature of mice and humans. Precursor cell populations, anatomical localization, morphology, phenotype, and functions determine the type of DC. However, the origin of different DC subsets is still controversial (4). A particular subset of DC is represented by Langerhans cells (LC), which are immature DC present in the epidermis and mucosal epithelium (53, 71). LC can be generated either from myeloid precursors (77, 78) or from CD4 low lymphoid precursors (2). LC express a number of cell surface receptors including CD205/DEC205, Fc␥ and Fcε receptors, and langerin/ CD207 (70,72).Langerin is a C-type lectin oriented in a type II configuration and featuring a single carbohydrate recognition domain in its extracellular region (72). Langerin molecules oligomerize as trimers at the cell surface and display Ca 2ϩ -dependent binding specificity for mannose, N-acetyl-glucosamine, and fucose (61, 72). Langerin is a potent inducer of Birbeck granules (BG), the hallmark organelles of LC, which consist of pentalamellar and zippered membranes at the electron microscopic level (12,75). In addition to inducing BG formation, langerin is an endocytic receptor involved in the trafficking of exogenous mannosylated ligands from the cell surface into intracellular BG compartments (71).To further explore the role of langerin and BG, we generated C57BL/6 mice with a targeted disruption of the langerin gene. Although MHC class II-positive LC were detected in n...
Accumulating evidence points to inflammation as a promoter of carcinogenesis. MyD88 is an adaptor molecule in TLR and IL-1R signaling that was recently implicated in tumorigenesis through proinflammatory mechanisms. Here we have shown that MyD88 is also required in a cell-autonomous fashion for RAS-mediated carcinogenesis in mice in vivo and for MAPK activation and transformation in vitro. Mechanistically, MyD88 bound to the key MAPK, Erk, and prevented its inactivation by its phosphatase, MKP3, thereby amplifying the activation of the canonical RAS pathway. The relevance of this mechanism to human neoplasia was suggested by the finding that MyD88 was overexpressed and interacted with activated Erk in primary human cancer tissues. Collectively, these results show that in addition to its role in inflammation, MyD88 plays what we believe to be a crucial direct role in RAS signaling, cell-cycle control, and cell transformation.
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