Increased Membrane Cholesterol in Lymphocytes Diverts T-Cells toward an Inflammatory Response

Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40–50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4+ Foxp3+ T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response

Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.Peer reviewe

Morphometry of right and left ventricular myocardium after strenuous exercise in preconditioned rats.

Young male rats were exposed to a biphasic training program in which a 7-week preconditioning period of moderate treadmill exercise was followed by 8 weeks of strenuous endurance running. In comparison with sedentary control animals, the trained rats at 20 weeks of age had developed myocardial hypertrophy of the right ventricle (20%) and interventricular septum (23%), but there was no difference in the weight of the left ventricular free wall. Myocyte hypertrophy (26%) in the right ventricle was achieved through an increase in mean cell length (24%) and the addition of new sarcomere units in series. Exercise induced no acceleration of capillary growth in either ventricle, leading to significant decreases in the capillary luminal volume density (-21%) and surface density (-16%) in the right ventricle. Such alterations in the structural properties of the microvasculature implicated in oxygen availability and diffusion suggest that vigorous exercise, even after a preconditioning period, may still be detrimental to the myocardium. The techniques of myocardial morphometry were examined with respect to potential errors associated with oblique tissue sections and the use of light versus electron microscopy for cell counting. It was shown that the practical effects of obliquity are negligible and that electron microscopic resolution is essential

Morphometry of right and left ventricular myocardium after strenuous exercise in preconditioned rats.

Young male rats were exposed to a biphasic training program in which a 7-week preconditioning period of moderate treadmill exercise was followed by 8 weeks of strenuous endurance running. In comparison with sedentary control animals, the trained rats at 20 weeks of age had developed myocardial hypertrophy of the right ventricle (20%) and interventricular septum (23%), but there was no difference in the weight of the left ventricular free wall. Myocyte hypertrophy (26%) in the right ventricle was achieved through an increase in mean cell length (24%) and the addition of new sarcomere units in series. Exercise induced no acceleration of capillary growth in either ventricle, leading to significant decreases in the capillary luminal volume density (-21%) and surface density (-16%) in the right ventricle. Such alterations in the structural properties of the microvasculature implicated in oxygen availability and diffusion suggest that vigorous exercise, even after a preconditioning period, may still be detrimental to the myocardium. The techniques of myocardial morphometry were examined with respect to potential errors associated with oblique tissue sections and the use of light versus electron microscopy for cell counting. It was shown that the practical effects of obliquity are negligible and that electron microscopic resolution is essential