Effects of epithelial IL-13Rα2 expression in inflammatory bowel disease

status: accepte

Activités agricoles et risque de cancers chez les affiliés du régime agricole -Résultats intermédiaires de l'étude AGRICAN (AGRIculture et CANcers)

Ce volume rassemble l'ensemble des travaux de recherche conduits dans le cadre des appels à projets soutenus par le plan Ecophyto, et présentés à l'occasion du colloque Ecophyto Recherche des 13 et 14 octobre 2015National audienceThe part of cancers attributable to occupational exposures represents at least 2 to 8 % of the mortality by cancer (that is 3 in 12,000 deaths a year in France). Literature on cancer risk among agricultural population is scarce in France although these exposures concern more than 1 million people and France is one of first user countries of pesticides in the World. Nevertheless, according to numerous studies led mainly among the North American and Scandinavian farmers, several cancers are morefrequent among farmers (hematological cancers, malignant melanoma, soft tissue sarcomas, prostate, stomach and brain cancer…), particularly among those exposed to pesticides. A very large cohort of farmers and agricultural workers is constituted since 2008. This cohort AGRICAN concerns departments having a cancer registry qualified by the National Committee of Registers, for an enrolment of more than 180,000 members of the agricultural health insurance (farm owners and farm workers mainly, active or retired). It makes of this cohort the vastest and the most varied in then populations and the agricultural activities concerned at the international level and one of the biggest cohort led in France. The first results in terms of mortality and incidence over the period between the enrolment (2005-2007) and the end of year 2011 confirm and strengthen the trends observed at the international level, worth knowing lower risks for smoking related cancers and increased risks for hematological cancers, cancers of the prostate, the lips and for the cutaneous melanomas. The first internal analyses on the most frequent cancers showed increased risks for prostate cancers among cattle breeders (in particular during the use of insecticides on animals), or of pigs or still during the realization of hays as well as during the direct or indirect pesticide exposure on various crops (wheat- barley, fruit growing, potatoes, tobacco) and more particularly to those having never worn protective gloves during the use of pesticides. Lung cancer was also increased among farmers involved in peas growing, especially during harvesting. Interestingly, our study provides evidence of strong andconsistent protective effect of cattle and horse farming on lung cancer, especially in individuals who cared or milked the animals, independently of smoking. The first phase of follow-up of the exposures in this cohort began in its active phase at the beginning of 2015 with the sending of self-administered questionnaires which will allow to update information on the occupational exposures and life habits.Collaborative works are in progress with several other agricultural cohorts at the international level within the framework of the international consortium of agricultural cohorts (AGRICOH), in particular, on the risk factors of hematological cancers (Norwegian and American cohorts) and on the matrix exposure on endotoxins (American, New Zealand cohorts).La part des cancers attribuable à des expositions professionnelles représenterait au minimum 2 à 8% de la mortalité par cancer (soit 3 à 12.000 décès par année en France). La population agricole a été très peu étudiée en France en particulier en termes de survenue de cancer bien que les expositions professionnelles en exploitation agricole concernent plus de 1 million de personnes et que la Francesoit un des premiers pays utilisateurs de pesticides au Monde. Pourtant, d’après de nombreuses études menées principalement chez les agriculteurs nord-américains et scandinaves, certains cancers (hémopathies malignes, cancers cutanés, sarcomes des tissus mous, cancer de la prostate, tumeurs cérébrales, cancers gastriques,…) sont retrouvés en excès dans cette profession et plus particulièrement chez les utilisateurs de pesticides. Une très vaste cohorte d’agriculteurs et de salariés agricoles est maintenant mise en place depuis 2008. Cette cohorte AGRICAN concerne des départements disposant d’un registre des cancers qualifié par le Comité National des Registres, pour une population incluse de plus de 180 000 affiliés du régimeagricole (chefs d’exploitation et ouvriers agricoles principalement, en activité ou retraités). Cela fait de cette cohorte la plus vaste et la plus variée dans les populations et les activités agricoles concernées au niveau international et une des plus grandes études de cohorte menée en France. Les premiers résultats en termes de mortalité et d’incidence sur la période entre l’inclusion (2005-2007) et la fin d’année 2011 confirment et renforcent les tendances observées au niveau international, à savoir desrisques plus faibles pour les cancers très liés au tabagisme et des risques augmentés pour des cancers hématologiques, de la prostate, des lèvres et pour les mélanomes cutanés. Les premières analyses internes sur les cancers les plus fréquents ont montré des risques augmentés de cancers de la prostate chez les éleveurs de bovins (notamment lors de l’utilisation d’insecticides sur animaux), ou de cochonsou encore lors de la réalisation des foins ainsi que lors de l’exposition directe ou indirecte aux pesticides sur différentes cultures (blé-orge, arboriculture, pommes de terre, tabac) et plus particulièrement chez ceux n’ayant jamais porté de gants de protection lors de l’utilisation de pesticides. De façon intéressante, notre étude fournit des éléments convaincants en faveur d’un fort effet protecteur de l’implication dans des élevages de bovins ou de chevaux sur le cancer du poumon, particulièrementchez les éleveurs impliqués dans l’alimentation ou la traite des vaches, et ceci en tenant compte du tabagisme. La première phase de suivi des expositions dans cette cohorte a débuté dans sa phase active en début 2015 par l’envoi d’auto-questionnaires de suivi qui permettront de mettre à jour des informations sur les expositions professionnelles et des habitudes de vie. Des travaux collaboratifs sont en cours avec plusieurs autres cohortes agricoles au niveau international dans le cadre du consortium international de cohortes agricoles (AGRICOH), notamment, sur les facteurs de risque de cancers hématologiques (cohortes norvégiennes et américaines), sur une matrice d’exposition aux endotoxines (cohortes américaines, néo-zélandaises…)

Effects of T cell-induced Colonic Inflammation on Epithelial Barrier Function

BACKGROUND: Epithelial barrier disturbance is thought to contribute to the pathogenesis of inflammatory bowel diseases; however, it remains unclear whether it is a primary defect participating to the onset of inflammation or only a consequence of sustained inflammation. METHODS: A time course study of epithelial barrier functions and immune mediators was performed in the CD4(+)CD45RB(hi) T cell transfer model of colitis using Ussing chambers. RESULTS: In nonreconstituted severe combined immunodeficiency (SCID) mice, no epithelial dysfunction was observed. However, after transfer of CD4(+)CD45RB(hi) T cells or total CD4(+) T cells, colon of SCID mice displayed a decreased epithelial resistance, even before overt microscopic inflammation had occurred. Sustained colitis of CD4(+)CD45RB(hi) T cell reconstituted mice was also associated with enhanced subepithelial resistance, enhanced paracellular permeability, and decreased net ion transport. All these reflect a disturbance of barrier function and may contribute to diarrhea. Epithelial resistance was positively correlated with interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta) levels and net ion transport inversely correlated with tumor necrosis factor alpha (TNF-alpha) levels, pointing to the protective effect of IL-10 and TGF-beta and to a damaging effect of TNF-alpha. Indomethacin, a nonselective COX inhibitor, decreased epithelial resistance independent of T cells and inflammation, but its effect was more pronounced in inflamed colon. CONCLUSIONS: Induction of colitis by transfer of CD4(+)CD45RB(hi) T cells in SCID mice leads to changes in the colonic epithelium before colitis develops. Decreased epithelium resistance might contribute to the development of colitis; however, it is not sufficient to lead to chronic inflammation.status: publishe

IL-15Rα expression in inflammatory bowel disease patients before and after normalization of inflammation with infliximab

Interleukin-15 (IL-15) is a pro-inflammatory cytokine suspected to contribute to the inflammation in inflammatory bowel diseases (IBD). The specific receptor chain IL-15Rα can be expressed as a transmembranous signaling receptor, or can be cleaved by a disintegrin and metalloprotease domain 17 (ADAM17) into a neutralizing, soluble receptor (sIL-15Rα). The aim of this study is to evaluate the expression of IL-15Rα in ulcerative colitis (UC) and Crohn's disease (CD) patients before and after infliximab (IFX) therapy. Gene expression of IL-15Rα, IL-15 and ADAM17 was measured at the mRNA level by quantitative reverse transcriptase PCR in mucosal biopsies harvested before and after first IFX therapy. Concentrations of sIL-15Rα were measured in sera of patients by ELISA and IL-15Rα protein was localized in the gut by immunohistochemistry and immunofluorescence. Mucosal expression of IL-15Rα is increased in UC and CD patients as compared to controls and it remains elevated after IFX therapy in both responder and non-responder patients. The concentration of sIL-15Rα in serum is also increased in UC patients when compared to controls and does not differ between responders and non-responders both before and after IFX. CD patients have levels of sIL-15Rα comparable to healthy controls before and after therapy. In mucosal tissues, IL-15Rα+ cells closely resemble activated memory B cells with a preplasmablastic phenotype. To conclude, IBD patients have an increased expression of IL-15Rα mRNA in the mucosa. Expression is localized in B cells, suggesting that IL-15 regulates B cell functions during bowel inflammation. No change in release of sIL-15Rα is observed in patients treated with IFX. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd.status: publishe

Hydration for health hypothesis : a narrative review of supporting evidence

Purpose: An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of optimal hydration. Methods: Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, complemented by manual search of article reference lists and the expertise of relevant practitioners for each area studied. Results: The available literature suggest the effects of increased water intake on health may be direct, due to increased urine flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease. Conclusion: In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5 L day−1 to allow for the daily excretion of 2 to 3 L of dilute (< 500 mOsm kg−1) urine. Simple urinary markers of hydration such as urine color or void frequency may be used to monitor and adjust intake