ABSTRACT
AIM: To assess whether polymorphisms in NOD2 and ATG16L1 affect cytokine responses and mycobacterium avium subspecies paratuberculosis (MAP) survival in monocytes from Crohn's disease (CD) patients. METHODS: Monocytes were isolated from peripheral blood of CD patients of known genotype for common single nucleotide polymorphisms of NOD2 and ATG16L1. Monocytes were challenged with MAP and bacterial persistence assessed at subsequent time-points. Cytokine responses were assayed using a Milliplex multi-analyte profiling assay for 13 cytokines. RESULTS: Monocytes heterozygous for a NOD2 polymorphism (R702W, P268S, or 1007fs) were more permissive for growth of MAP (P = 0.045) than those without. There was no effect of NOD2 genotype on subsequent cytokine expression. The T300A polymorphism of ATG16L1 did not affect growth of MAP in our model (P = 0.175), but did increase expression of cytokines interleukin (IL)-10 (P = 0.047) and IL-6 (P = 0.019). CONCLUSION: CD-associated polymorphisms affected the elimination of MAP from ex vivo monocytes (NOD2), or expression of certain cytokines (ATG16L1), implying independent but contributory roles in the pathogenesis of CD.
Subject(s)
Carrier Proteins/genetics , Crohn Disease/genetics , Crohn Disease/immunology , Monocytes/immunology , Nod2 Signaling Adaptor Protein/genetics , Polymorphism, Genetic , Autophagy-Related Proteins , Crohn Disease/microbiology , Cytokines/immunology , Female , Genotype , Humans , Male , Monocytes/microbiology , Mycobacterium avium subsp. paratuberculosis/physiologyABSTRACT
BACKGROUND: Soluble CD40 ligand (sCD40L) is a powerful marker of cardiovascular risk. Exercise is known to decrease cardiovascular risk, but the impact of ultra-endurance exercise on sCD40L responses is unknown. OBJECTIVE: To examine the relationship between ultra-endurance exercise in trained athletes and levels of sCD40L and its natural ligand sCD40. DESIGN: Control-trial, crossover design, exercise intervention study of sCD40L and sCD40 levels. SETTING: Outdoor exercise and laboratory testing, single centre study, School of Physical Education, University of Otago, New Zealand. PARTICIPANTS: Nine trained ultra-endurance athletes. INTERVENTIONS: Athletes exercised (cycled and jogged) for 17 of 24 h. Venous blood was sampled at baseline and serially throughout exercise and 24 and 48 h after exercise. The athletes completed a 24 h control trial on a separate occasion, in randomised order. MAIN OUTCOME MEASUREMENTS: Mean levels of sCD40L and sCD40 during exercise and rest with 95% CIs. RESULTS: sCD40L levels dropped steadily from baseline (median 4128 pg/ml) to a measured nadir at 24 h following exercise (median 1409 pg/ml) (p=0.01). The levels had started to rise again by 48 h after exercise. When measured as a group, sCD40L levels remained constant during a control rest period. sCD40 levels remained constant on both exercise and control days. CONCLUSION: Ultra-endurance exercise lowers the levels of the cardiovascular risk marker sCD40L in athletes. These results raise the possibility that exercise-induced changes in sCD40L may provide one of the mechanisms by which exercise lowers cardiovascular risk.
