Ser276 Phosphorylation of NF-kB p65 by MSK1 Controls SCF Expression in Inflammation

Transcription of the mast cell growth factor SCF (stem cell factor) is upregulated in inflammatory conditions, and this is dependent upon NF-κB, as well as the MAP kinases p38 and ERK activation. We show here that the MAPK downstream nuclear kinase MSK1 induces NF-κB p65 Ser276 phosphorylation upon IL-1ß treatment, which was inhibited in cells transfected with a MSK1 kinase-dead (KD) mutant compared to the WT control. In addition, we show by ChIP experiments that MSK1 as well as MAPK inhibition abolishes binding of p65, of its coactivator CBP, and of MSK1 itself to the κB intronic enhancer site of the SCF gene. We show that interaction between NF-κB and CBP is prevented in cells transfected by a p65 S276C mutant. Finally, we demonstrate that both transfections of MSK1-KD and MSK1 siRNA - but not the WT MSK1 or control siRNA - downregulate the expression of SCF induced by IL-1ß. Our study provides therefore a direct link between MSK1-mediated phosphorylation of Ser276 p65 of NF-κB, allowing its binding to the SCF intronic enhancer, and pathophysiological SCF expression in inflammation

Guide de poche des dendro-microhabitats : Description des différents types de microhabitats liés aux arbres et des principales espèces qui y sont associées

Le feuillage des arbres est bien connu pour offrir un abri aux oiseaux, écureuils et autres espèces aisément observables. Mais les arbres recèlent, sur le tronc et les branches, une foule d’autres structures, de taille souvent modeste, qui fournissent abri, nourriture ou lieu de reproduction à une grande diversité d’espèces parmi les animaux, les végétaux ou les champignons. Ces milieux de vie de petite taille portés par les arbres sont appelés «dendro-microhabitats» (fig. 1). Les dendro-microhabitats(en abrégé: «dmh») présentent, selon leur nature (arbre support vivant ou mort, localisation dans l’arbre, forme, degré de décomposition du bois,...), des conditions de vie très différentes les unes des autres. Chaque type de dmh abrite par conséquent des espèces bien spécifiques. Plus on compte de types de dmh dans un peuplement, plus on multiplie les milieux de vie et donc la capacité du peuplement à accueillir un grand nombre d’espèces. Comme les dmh sont des milieux de vie spatialement isolés et évolutifs, les espèces associées sont obligées de se déplacer à travers le peuplement pour trouver un dmh similaire, afin de réduire le parasitisme et le risque de prédation, de rencontrer d’autres individus pour se reproduire ou, bien sûr, pour remplacer le dmh disparu. Ainsi, la fréquence d’un même type de dmh est également très importante pour la survie des espèces associées à ce type. Pour conserver une grande diversité d’espèces en forêt et ainsi renforcer la résistance et la résilience du peuplement, il est donc très utile d’apprendre à reconnaître les dmh. Cela permet d’être à même de repérer les arbres-habitats à conserver lors du martelage ou d’estimer la capacité d’accueil potentielle du peuplement pour les espèces

The economic burden of asthma prior to death: a nationwide descriptive study

BackgroundIn addition to the clinical burden, asthma is responsible for a high economic burden. However, little is known about the economic burden of asthma prior to death.ObjectiveWe performed an economic analysis to describe the costs during 12 and 24 months prior to asthma death between 2013 and 2017 in France.MethodsAn observational cohort study was established using the French national health insurance database. Direct medical and non-medical costs, as well as costs related to absence from the workplace, were included in the analysis.ResultsIn total, 3,829 patients were included in the final analysis. Over 24 and 12 months prior to death, total medical costs per patient were €27,542 [26,545–28,641] and €16,815 [16,164–17,545], respectively. Total medical costs clearly increased over 24 months prior to death. Over 12 months prior to death, costs increased significantly according to age categories, with mean total costs of €8,592, €15,038, and €17,845, respectively, for the categories <18 years old, 18–75 years old, and 75+ years old (p < 0.0001). Over 12 months prior to death, costs were statistically higher in patients with a dispensation of six or more SABA canisters compared to those with a dispensation of five or less canisters (p < 0.0001). In multivariate analysis, comorbidities, hospital as location of death, and dispensation of 12 or more canisters of SABA per year are independent factors of the highest costs.ConclusionTo conclude, the economic burden of asthma death is high and increases with time, age, and SABA dispensation

Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT

International audienceBackground: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT. Methodology/Principal Findings: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200 ± 40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150 ± 80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant. Conclusions: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicit

Pharmacological approaches to target type 2 cytokines in asthma

Asthma is the most common chronic lung disease, affecting more than 250 million people worldwide. The heterogeneity of asthma phenotypes represents a challenge for adequate assessment and treatment of the disease. However, approximately 50% of asthma patients present with chronic type 2 inflammation initiated by alarmins, such as IL-33 and thymic stromal lymphopoietin (TSLP), and driven by the TH2 interleukins IL-4, IL-5 and IL-13. These cytokines have therefore become important therapeutic targets in asthma. Here, we discuss current knowledge on the structure and functions of these cytokines in asthma. We review preclinical and clinical data obtained with monoclonal antibodies (mAbs) targeting these cytokines or their receptors, as well as novel strategies under development, including bispecific mAbs, designed ankyrin repeat proteins (DARPins), small molecule inhibitors and vaccines targeting type 2 cytokines

Implication des mastocytes et de la voieSCF/c-Kit dans l'inflammation et le remodelage dans l'asthme et la fibrose pulmonaire

Le stem cell factor (SCF) est le principal facteur de croissance des mastocytes. Nous avons montré que l expression du SCF est sous la dépendance de la kinase nucléaire MSK1. Cette kinase est activée par les MAP kinases p38 et ERK en conditions inflammatoires. Une fois activée, MSK1 phosphoryle la Ser276 de la sous-unité p65 de NF- B, permettant à NF- B d interagir avec son complexe co-activateur CBP et de se lier au 1er intron du gène codant le SCF. Nous avons ensuite étudié l implication des mastocytes dans des modèles murins d asthme chronique et fibrose. Nous avons pour cela comparé les réponses de souris sauvages et déficientes en mastocytes (KitWsh/Wsh), ayant ou pas subit un transfert adoptif de mastocytes dérivés de moelle osseuse. Nous avons ainsi pu montrer que le mastocyte joue un rôle central dans l établissement d une hyperréactivité bronchique et d un remodelage bronchique, dans les mécanismes de fibrose pulmonaire et dans l infiltration de cellules inflammatoires.Stem cell factor (SCF) is one of the major mast cell growth factor. We found that SCF expression is controlled by the nuclear kinase MSK1. This kinase is activated by both the p38 and ERK MAP kinases in inflammatory conditions and phosphorylate the p65 subunit of NF- B. This phosphorylation occurs at Ser276 and regulates both the binding of NF- B to its coactivator CBP and to the first intron of the SCF gene. We next studied the implication of mast cells in murine models of chronic asthma and lung fibrosis. To do so, we compared the responses of wildtype mice to those of mast cell-deficient mice (KitWsh/Wsh mice), before and after adoptive transfert of bone marrow-derived cultured mast cells. We showed that mast cells play a key role in bronchial hyperresponsiveness and remodeling, as well as in pulmonary fibrosis and infiltration of inflammatory cells.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Combining Anti-IgE Monoclonal Antibodies and Oral Immunotherapy for the Treatment of Food Allergy

International audienceImmunoglobulin E (IgE)-mediated food allergy is a real public health problem worldwide. The prevalence of food allergy is particularly high in children. Patients with food allergy experience high morbidity with a change in quality of life due to the risk of severe anaphylaxis. Current treatment options are poor. Allergen avoidance is widely recommended but exposes patients to accidental ingestion. Oral immunotherapy is also used in patients with food allergies to the most common allergens. Oral immunotherapy consists of a daily administration of small, gradually increasing amounts of allergens to induce desensitisation. This procedure aims at inducing immune tolerance to the ingested food allergens. However, some patients experience adverse reactions and discontinue oral immunotherapy.Given that IgE plays a crucial role in food allergy and anti-IgE are effective in allergic asthma, the use of anti-IgE therapeutic monoclonal antibodies (mAbs) such as omalizumab has been assessed in food allergy patients. The use of omalizumab as a monotherapy in food allergy has not been extensively studied but looks promising. There is more published evidence regarding the effect of omalizumab and oral immunotherapy in food allergy. Given the promising results of oral immunotherapy regarding sustained tolerance in clinical trials and the potential capacity of omalizumab to reduce symptoms in case of accidental exposure, a strategy combining oral immunotherapy with omalizumab pre-treatment has been suggested as a safer option in patients with severe food allergy compared to isolated therapy. Omalizumab seems useful in ensuring safer administration of oral immunotherapy with the oral immunotherapy maintenance dose being reached more rapidly. Quality-of-life improvement is greater with oral immunotherapy + omalizumab compared to oral immunotherapy alone. Moreover, sustained unresponsiveness is achieved more frequently with omalizumab. Considering that precision medicine and personalised therapy are major goals for allergic diseases, predictive biomarkers are crucial in order to identify food allergy patients more likely to benefit from anti-IgE therapies