Highlights • TNF family cytokines activate both canonical and noncanonical NF-κB signaling pathways. • TNF/TNFR1 signaling serves as a model of the canonical NF-κB pathway. • CD40L/CD40 signaling ...serves as a model of the noncanonical NF-κB pathway. • The molecular mechanisms linking ligation of TNFR1 or CD40 to activation of the canonical or noncanonical NF-κB signaling pathway remain unclear.
The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal ...development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.
NF-κB transcription factors are critical regulators of immunity, stress responses, apoptosis and differentiation. A variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied ...transcriptional programs. Consequently, NF-κB-dependent transcription is not only tightly controlled by positive and negative regulatory mechanisms but also closely coordinated with other signaling pathways. This intricate crosstalk is crucial to shaping the diverse biological functions of NF-κB into cell type- and context-specific responses.
NF-κB in immunobiology Hayden, Matthew S; Ghosh, Sankar
Cell research,
02/2011, Letnik:
21, Številka:
2
Journal Article
Recenzirano
Odprti dostop
NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system. Thus, it is not surprising that the clearest biological role of NF-κB ...is in the development and function of the immune system. Both innate and adaptive immune responses as well as the development and maintenance of the cells and tissues that comprise the immune system are, at multiple steps, under the control of the NF-κB family of transcription factors. Although this is a well-studied area of NF-κB research, new and significant findings continue to accumulate. This review will focus on these areas of recent progress while also providing a broad overview of the roles of NF-κB in mammalian immunobiology.
New regulators of NF-κB in inflammation Ghosh, Sankar; Hayden, Matthew S
Nature reviews. Immunology,
200811, 2008-11-00, 20081101, Letnik:
8, Številka:
11
Journal Article
Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized ...in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11−/− mice are efficiently infected with orally administered S. Typhi. We also find that tlr11−/− mice can be immunized against S. Typhi. Therefore, tlr11−/− mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen.
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▸ TLR11 is expressed in mouse intestine and recognizes Salmonella flagellin ▸ Tlr11−/− mice are susceptible to S. Typhi infection and model typhoid fever ▸ Immunization protects Tlr11−/− mice from S. Typhi infection ▸ Tlr11−/− mice show human-like symptoms, modeling infection to inform vaccine strategies
Tlr11 knockout mice are susceptible to S. Typhi infection and model human typhoid fever, providing the opportunity to test vaccine strategies in an animal model.
Toll-like receptor 11 (TLR11) recognizes T. gondii profilin (TgPRF) and is required for interleukin-12 production and induction of immune responses that limit cyst burden in Toxoplasma ...gondii-infected mice. However, TLR11 only modestly affects survival of T. gondii-challenged mice. We report that TLR12, a previously uncharacterized TLR, also recognized TgPRF. TLR12 was sufficient for recognition of TgPRF by plasmacytoid dendritic cells (pDCs), whereas TLR11 and TLR12 were both required in macrophages and conventional DCs. In contrast to TLR11, TLR12-deficient mice succumb rapidly to T. gondii infection. TLR12-dependent induction of IL-12 and IFN-α in pDCs led to production of IFN-γ by NK cells. Consistent with this observation, the partial resistance of Tlr11−/− mice is lost upon pDC or NK cell depletion. Thus, TLR12 is critical for the innate immune response to T. gondii, and this TLR may promote host resistance by triggering pDC and NK cell function.
► TLR12 is critical for protection against Toxoplasma gondii ► TLR12 recognizes profilin, the same ligand from T. gondii recognized by TLR11 ► TLR11 and TLR12 can act as heterodimers ► TLR12 triggers activation of pDC and NK cells upon T. gondii infection
Metabolic disorders including obesity, type 2 diabetes, and atherosclerosis have been viewed historically as lipid storage disorders brought about by overnutrition. It is now widely appreciated that ...chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases. Consistent with its central role in coordinating inflammatory responses, numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology and offering hope for the development of new therapeutic approaches for their treatment.
The Human Gene Mutation Database (HGMD
®
) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited ...disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central unified gene/disease-oriented repository of heritable mutations causing human genetic disease used worldwide by researchers, clinicians, diagnostic laboratories and genetic counsellors, and is an essential tool for the annotation of next-generation sequencing data. The public version of HGMD (
http://www.hgmd.org
) is freely available to registered users from academic institutions and non-profit organisations whilst the subscription version (HGMD Professional) is available to academic, clinical and commercial users under license via QIAGEN Inc.
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