No abstract is provided for this article.
In 2011, the Nobel Prize in Physiology or Medicine was awarded to three immunologists: Bruce A. Beutler, Jules A. Hoffmann, and Ralph M. Steinman. While Steinman was honored for his work on dendritic cells and adaptive immunity, Beutler and Hoffman received the prize for their contributions to discoveries in innate immunity. In 1996, Hoffmann found the toll gene to be crucial for mounting antimicrobial responses in fruit flies, first implicating this developmental gene in immune signaling. Two years later, Beutler built on this observation by describing a Toll-like gene, tlr4, as the receptor for the bacterial product LPS, representing a crucial step in innate immune activation and protection from bacterial infections in mammals. These publications spearheaded research in innate immune sensing and sparked a huge interest regarding innate defense mechanisms in the following years and decades. Today, Beutler and Hoffmann’s research has not only resulted in the discovery of the role of multiple TLRs in innate immunity but also in a much broader understanding of the molecular components of the innate immune system. In this review, we aim to collect the discoveries leading up to the publications of Beutler and Hoffmann, taking a close look at how early advances in both developmental biology and immunology converged into the research awarded with the Nobel Prize. We will also discuss how these discoveries influenced future research and highlight the importance they hold today.
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No abstract is provided for this article.
The role of ceramide as a second messenger in tumor necrosis factor (TNF)-mediated signal transduction has been much debated. It is supported by recent reports describing an expanding number of potential targets for this lipid, but is opposed by those describing how ceramide is not necessary for many TNF-mediated cellular events. In this paper, we directly compare the effects of the cell-permeable ceramide analogue, N-acetylsphingosine (C2-ceramide), with TNF, on NFkappaB function, a transcription factor whose activation is central to many TNF-mediated effects. We describe how C2-ceramide failed to drive kappaB-linked chloramphenicol acetyltransferase gene expression in either HL60 promyelocytic or Jurkat T lymphoma cells. Furthermore, it had no effect on TNF-mediated transcription of this reporter gene. However, electrophoretic mobility shift analysis following cell stimulation with this ceramide analogue revealed a dose-responsive activation of NFkappaB, which was not apparent following cell treatment with the inactive dihydro form. Activated complexes from treated cells were shown to contain predominantly the p50 subunit, in contrast to complexes from TNF-treated cells, where both p50 and p65/RelA subunits were present. The specific activation of p50 homodimeric complexes by C2-ceramide, which are known to lack trans-activating activity, was strongly suggested from these data. Further investigations revealed that C2-ceramide had only a marginal effect on IkappaBalpha degradation but strongly promoted the processing of p105 to its p50 product as revealed by immunoblot analysis. The increase in p50 arising from the processing of its p105 precursor was further established from p105/p50 ratios obtained by scanning densitometric analysis of bands from immunoblots. TNF, on the other hand, stimulated both IkappaBalpha degradation and p105 processing, in accordance with previous findings. Furthermore, the effect of TNF on NFkappaB activation was rapid, whereas C2-ceramide required an optimal treatment time of 1 h. Interestingly, TNF was found to increase ceramide in cells but only after a 1-h contact time. Our data therefore suggest that ceramide promotes the activation of NFkappaB complexes that lack transactivating activity by enhanced processing of p105.
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No abstract is provided for this article.
The Nlrp3 inflammasome is a key controller of the proinflammatory cytokine IL-1β. Iyer and colleagues (2013) demonstrate that Nlrp3 activators promote an interaction between cardiolipin in mitochondria and Nlrp3. Cardiolipin is thus a hydrophobic danger signal that, upon translocation to the outer mitochondrial membrane, activates Nlrp3, promoting inflammation.
Tricarboxylic acid (TCA) cycle metabolites have been implicated in modulating signalling pathways in immune cells. Notable examples include succinate and itaconate, which have pro- and anti-inflammatory roles, respectively. Recently, fumarate has emerged as having specific roles in macrophage activation, regulating the production of such cytokines as interleukin (IL)-10 and type I interferons (IFNs). Fumarate hydratase (FH) has been identified as a control point. Notably, FH loss in different models and cell types has been found to lead to DNA and RNA release from mitochondria which are sensed by cytosolic nucleic acid sensors including retinoic acid-inducible gene (RIG)-I, melanoma differentiation-associated protein (MDA)5, and cyclic GMP-AMP synthase (cGAS) to upregulate IFN-β production. These findings may have relevance in the pathogenesis and treatment of diseases associated with decreased FH levels such as systemic lupus erythematosus (SLE) or FH-deficient kidney cancer.
No abstract is provided for this article.
We report the protective effects of two novel anti-oxidant compounds, 3 β-doxyl-5 α cholestane and 2,2,6,6-tetramethyl-piperdinoxyl, in HL-60 and U937 leukemic cells subjected to a number of cytotoxic insults. In addition, the rapid production of peroxide is demonstrated as a general response to cytotoxic agents in these leukemic cell lines, indicating that changes in the redox status of a leukemic cell may contribute to the ultimate death of these cells. Closer examination of this peroxide production has identified enzymic production and/or disruption of resident anti-oxidants as possible sources. However, in contrast to recent reports from other model systems, mitochondrial transmembrane depolarization did not appear to be required for the production of peroxide in these cells. Finally, we demonstrated the activation of the redox-sensitive transcription factor, NF-κB, in response to these cytotoxic insults.
No abstract is provided for this article.
