The role of IKK-induced NF-kB1 p105 proteolysis in T lymphocytes

Proteolysis of NF-kB1 p105 is vital for its function as a precursor to p50 and as an IkB. This occurs in two ways, both mediated by the proteasome. A constitutive proteolytic removal of the p105 C-terminus, termed processing, generates the mature transcription factor p50. In contrast, a signal-induced p105 proteolysis is triggered by phosphorylation of serines 927 and 932 in the p105 PEST region by the IKK complex. This promotes p105 poly-ubiquitination and subsequent complete degradation. IKK-induced p105 proteolysis has been demonstrated to regulate the kinase activity of the MAP3K TPL-2, since all detectable TPL-2 is found in a complex with p105. Furthermore, NF-kB1 p105 retains Rel subunits in the cytoplasm via interaction with the p105 C-terminal ankyrin repeat region. However, it is unclear whether IKK-induced p105 proteolysis contributes to NF-kB activation, though this process would be expected to release Rel subunits to translocate into the nucleus. A large body of evidence exists to suggest a major role for NF-kB in T cell development and function. To investigate the significance of IKK-induced p105 degradation in T cells, a knock-in mouse strain, Nfkb1S927A'S93ZA, in which serines 927 and 932 of NF-kB1 p105 were mutated to alanine residues was analysed. Previous work has shown that constitutive processing of pio5S927A S932A to p50 occurs normally, but this mutated p105 is refractory to IKK-induced proteolysis. Work presented here demonstrates that whilst p105 mutation did not affect thymic differentiation of CD4+ and CD8+ T cells, numbers of CD4+CD25+ regulatory T cells, memory-phenotype CD4+ T cells and thymic NKT cells were significantly reduced. Analysis of BM chimeras revealed cell autonomous and non-haematopoietic defects required for generation of these sub-populations. In vitro experiments indicated that TCR-induced proliferation was significantly impaired in /Vflcb7S927A S932A CD4+ T cells, due partly to reduced interleukin-2 production. In contrast, p105 mutation had no effect on CD4+ T cell survival. These defects were not due to a lack of TPL-2 activity, based on analysis of TPL-2-deficient mice. This study presents evidence to suggest a critical role for IKK-induced p105 proteolysis in regulating NF-kB activation in T lymphocytes

Tissue Specific Deletion of Inhibitor of Kappa B Kinase 2 with OX40-Cre Reveals the Unanticipated Expression from the OX40 Locus in Skin Epidermis

NF-κB signalling plays an essential role in T cell activation and generation of regulatory and memory populations in vivo. In the present study, we aimed to investigate the role of NF-κB signalling in post-activation T cells using tissue specific ablation of inhibitor of kappa-B kinase 2 expression, an important component of the inhibitor of kappa-B kinase complex in canonical NF-κB signalling. The OX40 antigen is expressed on activated T cells. Therefore, we used previously described mouse strain expressing Cre recombinase from the endogenous OX40 locus. Ablation of IKK2 expression using OX40Cre mice resulted in the development of an inflammatory response in the skin epidermis causing wide spread skin lesions. The inflammatory response was characterised by extensive leukocytic infiltrate in skin tissue, hyperplasia of draining lymph nodes and widespread activation in the T cell compartment. Surprisingly, disease development did not depend on T cells but was rather associated with an unanticipated expression of Cre in skin epidermis, and activation of the T cell compartment did not require Ikbk2 deletion in T cells. Employment of Cre reporter strains revealed extensive Cre activity in skin epidermis. Therefore, development of skin lesions was rather more likely explained by deletion of Ikbk2 in skin keratinocytes in OX40Cre mice

Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice

regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)/CD28 stimulation along with cytokine-promoted Foxp3 induction. TCR-mediated nuclear factor kappa B (NF-κB) activation seems to be involved in differentiation of Treg cells because deletion of components of the NF-κB signaling pathway, as well as of NF-κB transcription factors, leads to markedly decreased Treg cell numbers in thymus and periphery. thymic Treg precursors and their further differentiation into mature Treg cells. Treg cell development could neither be completely rescued by the addition of exogenous Interleukin 2 (IL-2) nor by the presence of wild-type derived cells in adoptive transfer experiments. However, peripheral NF-κB activation appears to be required for IL-2 production by conventional T cells, thereby participating in Treg cell homeostasis. Moreover, pharmacological NF-κB inhibition via the IκB kinase β (IKKβ) inhibitor AS602868 led to markedly diminished thymic and peripheral Treg cell frequencies.Our results indicate that Treg cell-intrinsic NF-κB activation is essential for thymic Treg cell differentiation, and further suggest pharmacological NF-κB inhibition as a potential therapeutic approach for manipulating this process

Rising atmospheric methane: 2007-2014 growth and isotopic shift

From 2007 to 2013, the globally averaged mole fraction of methane in the atmosphere increased by 5.7±1.2ppb yr$^{-1}$. Simultaneously, $\delta^{13}$C$_\text{CH4}$ (a measure of the $^{13}$C/$^{12}$C isotope ratio in methane) has shifted to significantly more negative values since 2007. Growth was extreme in 2014, at 12.5±0.4ppb, with a further shift to more negative values being observed at most latitudes. The isotopic evidence presented here suggests that the methane rise was dominated by significant increases in biogenic methane emissions, particularly in the tropics, for example, from expansion of tropical wetlands in years with strongly positive rainfall anomalies or emissions from increased agricultural sources such as ruminants and rice paddies. Changes in the removal rate of methane by the OH radical have not been seen in other tracers of atmospheric chemistry and do not appear to explain short-term variations in methane. Fossil fuel emissions may also have grown, but the sustained shift to more $^{13}$C-depleted values and its significant interannual variability, and the tropical and Southern Hemisphere loci of post-2007 growth, both indicate that fossil fuel emissions have not been the dominant factor driving the increase. A major cause of increased tropical wetland and tropical agricultural methane emissions, the likely major contributors to growth, may be their responses to meteorological change.This work was supported by the UK Natural Environment Research Council projects NE/N016211/1 The Global Methane Budget, NE/M005836/1 Methane at the edge, NE/K006045/1 The Southern Methane Anomaly and NE/I028874/1 MAMM. We thank the UK Meteorological Office for flask collection and hosting the continuous measurement at Ascension, the Ascension Island Government for essential support, and Thumeka Mkololo for flask collection in Cape Tow

Understanding the complex interplay of barriers to physical activity amongst black and minority ethnic groups in the United Kingdom:a qualitative synthesis using meta-ethnography

BACKGROUND: To conduct a meta-ethnographic analysis of qualitative studies to identify barriers to Black and Minority Ethnic (BME) individuals engaging in physical activity in the UK context.METHODS: A qualitative synthesis using meta-ethnographic methods to synthesis studies of barriers to engaging in physical activity among BME groups in the UK. A comprehensive search strategy of multiple databases was employed to identify qualitative research studies published up to October 2012. The eleven searched databases included ASSIA, MEDLINE, EMBASE, CINAHL, Health Technology Assessment (HTA), NHS Scotland Library, Physical Activity Health Alliance (PAHA), PsyINFO, Social Services Abstract, Sport discuss and Web of Science. The Noblit and Hare's meta-ethnographic approach was undertaken to develop an inductive and interpretive form of knowledge synthesis.RESULTS: Fourteen papers met the inclusion criteria. The synthesis indicated that barriers to physical activity among BME individuals were influenced by four main concepts: perceptions; cultural expectations; personal barriers; and factors limiting access to facilities. BME individuals had different understandings of physical activity were influenced by migration history, experiences, cultural and health beliefs. This in turn may have a disempowering effect on BME individuals in terms of adopting or maintaining physical activity. These barriers to physical activity were explained at a higher conceptual level by a socio-ecological model. The social construct 'individual perception and understanding of physical activity' was particularly relevant to theoretical models and interventions.CONCLUSION: Interventions to promote engagement with physical activity need to address perceptions of this behaviour. The elicited concepts and contexts could be used to enhance the development of tailored effective health promotion interventions for BME individuals

Obituary: Kuan-Teh Jeang.

Dear colleagues: Our loyal friend Kuan-Teh Jeang, "Teh" to friends and colleagues, passed away unexpectedly at the age of 54 on the evening of January 27, 2013. Great shock and sorrow was apparent in the avalanche of email messages by the very many international colleagues with whom Teh interacted over the years. Many of us came to know Teh as an energetic and gifted scientist for whom we had much respect and affection

Obituary: Kuan-Teh Jeang.

Dear colleagues: Our loyal friend Kuan-Teh Jeang, "Teh" to friends and colleagues, passed away unexpectedly at the age of 54 on the evening of January 27, 2013. Great shock and sorrow was apparent in the avalanche of email messages by the very many international colleagues with whom Teh interacted over the years. Many of us came to know Teh as an energetic and gifted scientist for whom we had much respect and affection

Tumor progression locus 2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells

BackgroundThe molecular and cellular pathways driving the pathogenesis of severe asthma are poorly defined. Tumor progression locus 2 (TPL-2) (COT, MAP3K8) kinase activates the MEK1/2-extracellular-signal regulated kinase 1/2 MAP kinase signaling pathway following Toll-like receptor, TNFR1, and IL-1R stimulation.ObjectiveTPL-2 has been widely described as a critical regulator of inflammation, and we sought to investigate the role of TPL-2 in house dust mite (HDM)-mediated allergic airway inflammation.MethodsA comparative analysis of wild-type and Map3k8−/− mice was conducted. Mixed bone marrow chimeras, conditional knockout mice, and adoptive transfer models were also used. Differential cell counts were performed on the bronchoalveolar lavage fluid, followed by histological analysis of lung sections. Flow cytometry and quantitative PCR was used to measure type 2 cytokines. ELISA was used to assess the production of IgE, type 2 cytokines, and Ccl24. RNA sequencing was used to characterize dendritic cell (DC) transcripts.ResultsTPL-2 deficiency led to exacerbated HDM-induced airway allergy, with increased airway and tissue eosinophilia, lung inflammation, and IL-4, IL-5, IL-13, and IgE production. Increased airway allergic responses in Map3k8−/− mice were not due to a cell-intrinsic role for TPL-2 in T cells, B cells, or LysM+ cells but due to a regulatory role for TPL-2 in DCs. TPL-2 inhibited Ccl24 expression in lung DCs, and blockade of Ccl24 prevented the exaggerated airway eosinophilia and lung inflammation in mice given HDM-pulsed Map3k8−/− DCs.ConclusionsTPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice

Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism

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