Role of endogenous IFN-gamma in macrophage programming induced by IL-12 and IL-18.

Besides the established role of interleukin-12 (IL-12) and IL-18 on interferon-gamma (IFN-gamma) production by natural killer (NK), T, and B cells, the effects of these cytokines on macrophages are largely unknown. Here, we investigated the role of IL-12/IL-18 on nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) production by CD11b(+) adherent peritoneal cells, focusing on the involvement of endogenously produced IFN-gamma. C57BL/6 cells released substantial amounts of NO when stimulated with IFN-gamma or lipopolysaccharide (LPS), but failed to respond to IL-12 or IL-18 or both. However, IL-12/IL-18 pretreatment was able to program these cells to release 6-8-fold more NO and TNF-alpha in response to LPS or Trypanosoma cruzi stimulation, with NO levels directly correlating with macrophage resistance to intracellular parasite growth. Analysis of IL-12/IL-18-primed cells from mice deficient in IFN-gamma, IFNGR, and IFN regulatory factor-1 (IRF-1) revealed that these molecules were essential for LPS-induced NO release, but TNF-alpha production was IFN-gamma independent. Conversely, the myeloid differentiation factor 88 (MyD88)-dependent pathway was indispensable for IL-12/IL-18-programmed LPS-induced TNF-alpha production, but not for NO release. Contaminant T and NK cells largely modulated the IL-12/IL-18 programming of LPS-induced NO response through IFN-gamma secretion. Nevertheless, a small population of IFN-gamma(+) cells with a macrophage phenotype was also identified, particularly in the peritoneum of chronically T. cruzi-infected mice, reinforcing the notion that macrophages can be an alternative source of IFN-gamma. Taken together, our data contribute to elucidate the molecular basis of the IL-12/IL-18 autocrine pathway of macrophage activation, showing that endogenous IFN-gamma plays an important role in programming the NO response, whereas the TNF-alpha response occurs through an IFN-gamma-independent pathway.     

Impaired macrophage responses may contribute to exacerbation of blood-stage Plasmodium chabaudi chabaudi malaria in interleukin-12-deficient mice.

Aiming to clarify the role of endogenous interleukin-12 (IL-12) in protective immunity against blood stages of Plasmodium chabaudi chabaudi (AS), we evaluated the course of infection in IL-12p40 gene knockout (IL-12p40KO) and wild-type (WT) C57BL/6 mice, focusing (1) on the ability of T cells to develop adequate type 1 responses and (2) on the potentiality of macrophages to respond to parasites, interferon-gamma (IFN-gamma), or both. We observed that IL-12p40KO mice develop significantly higher parasitemias during the acute infection, although mice from both groups clear the parasites within a month and similarly eliminate a secondary challenge. Thus, fully protective immunity to P. c. chabaudi can be generated in the absence of IL-12. However, this cytokine may promote parasite control during the early phase of infection. The increased acute parasitemia of IL-12p40KO mice was associated with both impaired IFN-gamma and nitric oxide (NO) response by spleen cells. Because stimulation with recombinant IFN-gamma (rIFN-gamma) failed to improve the NO response in IL-12p40KO macrophages, we investigated whether these cells have an intrinsic defect. Analysis of peritoneal macrophages revealed that IL-12p40KO cells produce higher levels of transforming growth factor-beta1 (TGF-beta1) compared with WT cells and respond to infected erythrocytes or rIFN-gamma by releasing little NO. Moreover, IL-12p40KO macrophages had a severely impaired ability to internalize opsonized infected erythrocytes, suggesting that the low effector profile assumed by these cells may compromise antibody-mediated immunity. Taken together, our results support the idea that the absence of IL-12p40 not only affects IFN-gamma production but also has deep consequences in macrophage effector functions that may contribute to exacerbation of the early phase of P. c. chabaudi malaria.     

Sedentary behavior and physical activity are independently related to functional fitness in older adults

The last decades of life have been traditionally viewed as a time of inevitable disease and frailty. Sedentary living and physical activity may influence capacity to perform activities that are needed to maintain physical independence in daily living. A total of 117 males and 195 females, aged 65–103 years, were assessed for physical activity and sedentary time with accelerometers and for functional fitness with the Senior Fitness Test battery. Based on the individual scores for each fitness item, a Z-score was created. Associations between functional fitness with sedentary time and moderate-to-vigorous physical activity (MVPA) were analyzed. A negative association was found between the composite Z-score for functional fitness and the sedentary time, even adjusting for MVPA and other confounders. On the other hand, MVPA was positively associated with the composite Z-score for functional fitness, independently of the sedentary time. In conclusion elderly who spend more time in physical activity or less time in sedentary behaviors exhibit improved functional fitness and other confounders. The results reinforce the importance of promoting both the reduction of sedentary behaviors and the increase of MVPA in this age group, as it may interfere at older ages in order to preserve functional fitness and performance of daily functioning tasks.     

Pelvis width associated with bone mass distribution at the proximal femur in children 10–11 years old

Differences in skeletal geometry may generate different patterns of mechanical loading to bone. Impact and muscle loading during physical activity have been shown to influence skeletal geometry. The purpose of this study was to compare geometric measures of the pelvis and proximal femur (PF) of young children and to analyze the contribution and potential interaction of these geometric measures with physical activity on PF bone mass distribution. Participants were 149 girls and 145 boys, aged 10–11 years. Total body and left hip DXA scans were used to derive pelvic and PF geometric measures and PF bone mineral density (BMD) at the femoral neck (FN), trochanter (TR), and intertrochanter (IT). These subregions were used to represent bone mass distribution via three BMD ratios: FN:PF, TR:PF, and IT:PF. Physical activity was objectively measured using accelerometry, and maturity was estimated as the years of distance from peak height velocity. When compared to boys, girls had a wider pelvic diameter and greater interacetabular distances (p < 0.001), lower BMD at FN, TR, and IT (p < 0.05), and higher TR:PF (p < 0.001). After controlling for maturity, body height, and lean body mass, the interacetabular distance in girls explained 21.1 % (β = 0.713, p < 0.001) in TR:PF and 2.9 % (β = ?0.179, p = 0.031) in the IT:PF. Neck–shaft angle explained 5.6 % (β = ?0.265, p = 0.001) of the IT:PF and 3.1 % (β = 0.194, p = 0.018) of the FN:PF. In boys, FN axis length explained 2.9 % (β = 0.195, p = 0.040) of TR:PF. There was no main effect of physical activity or interaction effect with pelvic geometry in explaining BMD differences among the subregions of the PF. Even before sexual dimorphism, girls have a wider pelvis than boys, which accounted for proportionally greater BMD of the TR than other subregions of the PF.     

Risk for losing physical independence in older adults: The role of sedentary time,light, and moderate to vigorous physical activity

This study examined the association of a range of physical activity intensities and sedentary behavior with the risk of losing physical independence later in life in community-dwelling older adults. A total of 131 males and 240 females, aged 65–103 years, were enrolled. Physical activity (PA) and sedentary time were assessed with accelerometers and the risk for losing physical independence in later years was assessed with the self-reported composite physical function (CPF) scale adjusted for age. Participants were divided in two groups – high risk group (HRG) and low risk group (LRG), according current CPF. According to the multiple logistic regression analyses, sedentary time was not a significant predictor. The odds of a male participant being in the LRG were 12.19 times higher than those of a female (95% CI 5.06–29.39). Both, light PA (OR = 1.01; 95% CI 1.01–1.02) and MVPA (OR = 1.432; 95% CI 1.21–1.69) had a significant main effect on the risk of losing physical independence. Age and gender interacted with moderate to vigorous PA (MVPA) to predict the risk of losing physical independence. Thus, as age increases, participants that are more physically active became less likely (OR = 0.997; 95% CI 0.995–0.999) to be in the HRG than younger participants. Similarly, the odds of a physically active women being physical independent in later life are higher (OR = 0.94; 95% CI 0.91–0.96) than those of a physically active men. These new findings suggest that light PA, and MVPA are significantly associated with the risk of losing physical independence later in life, and age and gender combined with MVPA have an interaction effect on physical independence of older adults.     

Assessing the validity of body mass index standards in early postmenopausal women

OBJECTIVE: To examine the relationship between percentage of total body fat (%Fat) and body mass index (BMI) in early postmenopausal women and to evaluate the validity of the BMI standards for obesity established by the NIH. RESEARCH METHODS AND PROCEDURES: Three hundred seventeen healthy, sedentary, postmenopausal women (ages, 40 to 66 years; BMI, 18 to 35 kg/m(2); 3 to 10 years postmenopausal) participated in the study. Height, weight, BMI, and %Fat, as assessed by DXA, were measured. Receiver operating characteristic analysis was performed to evaluate the ability of BMI to discriminate obesity from non-obesity using 38%Fat as the criterion value. RESULTS: A moderately high relationship was observed between BMI and %Fat (r = 0.81; y = 1.41x + 2.65) with a SE of estimate of 3.9%. Eighty-one percent of other studies examined fell within 1 SE of estimate as derived from our study. Receiver operating characteristic analysis showed that BMI is a good diagnostic test for obesity. The cutoff for BMI corresponding to the criterion value of 38%Fat that maximized the sum of the sensitivity and specificity was 24.9 kg/m(2). The true-positive (sensitivity) and false-positive (1--specificity) rates were 84.4% and 14.6%, respectively. The area under the curve estimate for BMI was 0.914. DISCUSSION: There is a strong association between %Fat and BMI in postmenopausal women. Current NIH BMI-based classifications for obesity may be misleading based on currently proposed %Fat standards. BMI >25 kg/m(2) rather than BMI >30 kg/m(2) may be superior for diagnosing obesity in postmenopausal women.