Article

Fas/CD95-Induced Chemokines Can Serve as "Find-Me" Signals for Apoptotic Cells.

Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
Molecular cell (Impact Factor: 14.46). 02/2013; DOI: 10.1016/j.molcel.2013.01.025
Source: PubMed

ABSTRACT Apoptosis is commonly thought to represent an immunologically silent or even anti-inflammatory mode of cell death, resulting in cell clearance in the absence of explicit activation of the immune system. However, here we show that Fas/CD95-induced apoptosis is associated with the production of an array of cytokines and chemokines, including IL-6, IL-8, CXCL1, MCP-1, and GMCSF. Fas-induced production of MCP-1 and IL-8 promoted chemotaxis of phagocytes toward apoptotic cells, suggesting that these factors serve as "find-me" signals in this context. We also show that RIPK1 and IAPs are required for optimal production of cytokines and chemokines in response to Fas receptor stimulation. Consequently, a synthetic IAP antagonist potently suppressed Fas-dependent expression of multiple proinflammatory mediators and inhibited Fas-induced chemotaxis. Thus, in addition to provoking apoptosis, Fas receptor stimulation can trigger the secretion of chemotactic factors and other immunologically active proteins that can influence immune responsiveness toward dying cells.

Download full-text

Full-text

Available from: Conor Henry, Jan 27, 2014
3 Followers
 · 
171 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Microbial infection and tissue injury are well established as the two major drivers of inflammation. However, although it is well established that necrotic cell death can trigger or potentiate inflammation, precisely how this is achieved still remains relatively obscure. Certain molecules, which have been dubbed ‘damage-associated molecular patterns’ (DAMPs) or alarmins, are thought to promote inflammation upon release from necrotic cells. However, the precise nature and relative potency of DAMPs, compared to conventional pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs), remains unclear. How different modes of cell death impact on the immune system also requires further clarification. Apoptosis has long been regarded as a non-inflammatory or even anti-inflammatory mode of cell death, but recent studies suggest that this is not always the case. Necroptosis is a programmed form of necrosis that is engaged under certain conditions when caspase activation is blocked. Necroptosis is also regarded as a highly pro-inflammatory mode of cell death but there has been little explicit examination of this issue. Here we discuss the inflammatory implications of necrosis, necroptosis and apoptosis and some of the unresolved questions concerning how dead cells influence inflammatory responses.
    Biological Chemistry 08/2014; 395(10). DOI:10.1515/hsz-2014-0164 · 2.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease. However, it is becoming clear that many of the available anticancer drugs that have collectively saved millions of life-years mediate therapeutic effects by eliciting de novo or reactivating pre-existing tumor-specific immune responses. Here, we discuss the capacity of both conventional and targeted anticancer therapies to enhance the immunogenic properties of malignant cells and to stimulate immune effector cells, either directly or by subverting the immunosuppressive circuitries that preclude antitumor immune responses in cancer patients. Accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents relies on their capacity to influence the tumor-host interaction, tipping the balance toward the activation of an immune response specific for malignant cells. We surmise that the development of successful anticancer therapies will be improved and accelerated by the immunological characterization of candidate agents.
    Immunity 07/2013; 39(1):74-88. DOI:10.1016/j.immuni.2013.06.014 · 19.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There are many studies performed to assess the associations of CD95 A670G and G1377A polymorphisms with gastric cancer, and the association of CD95L T844C polymorphism with gastric cancer risk, but the data are remaining controversial. To get a comprehensive assessment of the association above, we performed a meta-analysis of published studies. PubMed, Embase, Web of Science, and Wanfang Medicine databases were searched for eligible studies. There were eight studies including 3,790 subjects on CD95 A670G polymorphism, eight studies including 4,563 subjects on CD95 G1377A polymorphism, and eight studies including 4,563 subjects on CD95L T844C polymorphism. Overall, CD95 G1377A polymorphism was associated with a significantly increased risk of gastric cancer (for AA versus GG: odds ratio (OR) = 1.24, 95 % confidence interval (95 % CI) = 1.02-1.52, P = 0.030; for AA versus GG + GA: OR = 1.27, 95 % CI = 1.05-1.53, P = 0.012). However, there were no associations of CD95 A670G and CD95L T844C polymorphisms with gastric cancer. Subgroup analysis by ethnicity found similar associations in Asians, but the associations in Caucasians were still unclear owing to the lack of relevant data. Therefore, the outcomes of this meta-analysis show that there is a significant association between CD95 G1377A polymorphism and risk of gastric cancer.
    Tumor Biology 05/2013; 34(4). DOI:10.1007/s13277-013-0773-4 · 2.84 Impact Factor