TNF-α-induced protein 3 is a key player in childhood asthma development and environment-mediated protection.

BACKGROUND: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-α-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, mediates environmentally induced asthma protection. OBJECTIVE: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. METHODS: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective" farms or LPS. NF-κB signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. RESULTS: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P < .05), reflecting their increased inflammatory status. Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatic patients and shifted NF-κB signaling-associated gene expression toward an anti-inflammatory state (P < .001). Farm/rural children had lower expression, indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school age had reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma. CONCLUSION: Our data indicate TNFAIP3 as a key regulator during childhood asthma development and its environmentally mediated protection. Because environmental dust exposure conferred the anti-inflammatory effects, it might represent a promising future agent for asthma prevention and treatment.

IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort.

BACKGROUND: IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. METHODS: Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4+ CD25high FOXP3+ Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years. RESULTS: rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95%CI = 1.02-3.08; OR = 1.79, 95%CI = 1.04-3.11) and CD4+ CD25high FOXP3+ Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004; p(LPS) = 0.005; p(U) = 0.001; p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p(rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs. CONCLUSIONS: IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.

Associations of Early Life Exposures and Environmental Factors With Asthma Among Children in Rural and Urban Areas of Guangdong, China.

BACKGROUND: Environmental factors may play important roles in asthma, but findings have been inconsistent. OBJECTIVE: The goal of this study was to determine the associations between early life exposures, environmental factors, and asthma in urban and rural children in southeast China. METHODS: A screening questionnaire survey was conducted in 7,164 children from urban Guangzhou and 6,087 from rural Conghua. In the second stage, subsamples of 854 children (419 from Guangzhou, 435 from Conghua) were recruited for a case-control study that included a detailed questionnaire enquiring on family history, early life environmental exposures, dietary habits, and laboratory tests (including histamine airway provocation testing, skin prick tests, and serum antibody analyses). House dust samples from 76 Guangzhou families and 80 Conghua families were obtained to analyze levels of endotoxins, house dust mites, and cockroach allergens. RESULTS: According to the screening survey, the prevalence of physician-diagnosed asthma was lower in children from Conghua (3.4%) than in those from Guangzhou (6.9%) (P < .001). A lower percentage of asthma was reported in rural subjects compared with urban subjects (2.8% vs. 29.4%; P < .001) in the case-control study. Atopy (OR, 1.91 [95% CI, 1.58-2.29]), parental atopy (OR, 2.49 [95% CI, 1.55-4.01]), hospitalization before 3 years of age (OR, 2.54 [95% CI, 1.37-4.70]), high consumption of milk products (OR, 1.68 [95% CI, 1.03-2.73]), and dust Dermatophagoides farinae group 1 allergen (OR, 1.71 [95% CI, 1.34-2.19]) were positively associated with asthma. Living in a crop-farming family at < 1 year of age (OR, 0.15 [95% CI, 0.08-0.32]) and dust endotoxin levels (OR, 0.69 [95% CI, 0.50-0.95]) were negatively associated with asthma. CONCLUSIONS: Rural children from an agricultural background exhibited a reduced risk of asthma. Early life exposure to crop farming and high environmental endotoxin levels might protect the children from asthma in southern China.

The rural-urban enigma of allergy: what can we learn from studies around the world?

Childhood asthma and related allergic conditions have become the most common chronic disorders in the Western world. Many studies from around the world have demonstrated an increasing trend of asthma prevalence over the last few decades (Lancet, 368, 2004, 733). A few recent reports also suggested that childhood asthma prevalence may be showing a plateau or even a decline in few developed countries. Given the rapid changes in the prevalence over a short period of time, environmental factors are the more likely candidates explaining such trend. One of the most consistent epidemiological findings was that subjects living in the rural areas had lower prevalence of allergies when compared to those from urban areas (Clin Exp Allergy 30, 2000, 187; Pediatr Pulmonol 44, 2009, 793). Clear understanding of the mechanisms of how the environmental determinants in the rural environment may affect the early immune system resulting in lower risk of allergies and asthma will facilitate the development of future primary preventive strategies. In this study, we review recent data from around the world and explore the epidemiology and mechanistic studies that may explain the rural-urban difference of allergies.

Proteomic analysis of human hepatoma cells expressing methionine adenosyltransferase I/III: Characterization of DDX3X as a target of S-adenosylmethionine.

Methionine adenosyltransferase I/III (MATI/III) synthesizes S-adenosylmethionine (SAM) in quiescent hepatocytes. Its activity is compromised in most liver diseases including liver cancer. Since SAM is a driver of hepatocytes fate we have studied the effect of re-expressing MAT1A in hepatoma Huh7 cells using proteomics. MAT1A expression leads to SAM levels close to those found in quiescent hepatocytes and induced apoptosis. Normalization of intracellular SAM induced alteration of 128 proteins identified by 2D-DIGE and gel-free methods, accounting for deregulation of central cellular functions including apoptosis, cell proliferation and survival. Human Dead-box protein 3 (DDX3X), a RNA helicase regulating RNA splicing, export, transcription and translation was down-regulated upon MAT1A expression. Our data support the regulation of DDX3X levels by SAM in a concentration and time dependent manner. Consistently, DDX3X arises as a primary target of SAM and a principal intermediate of its antitumoral effect. Based on the parallelism between SAM and DDX3X along the progression of liver disorders, and the results reported here, it is tempting to suggest that reduced SAM in the liver may lead to DDX3X up-regulation contributing to the pathogenic process and that replenishment of SAM might prove to have beneficial effects, at least in part by reducing DDX3X levels. This article is part of a Special Issue entitled: Proteomics: The clinical link.

A signature of six genes highlights defects on cell growth and specific metabolic pathways in murine and human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents a major health problem as it afflicts an increasing number of patients worldwide. Albeit most of the risk factors for HCC are known, this is a deadly syndrome with a life expectancy at the time of diagnosis of less than 1 year. Definition of the molecular principles governing the neoplastic transformation of the liver is an urgent need to facilitate the clinical management of patients, based on innovative methods to detect the disease in its early stages and on more efficient therapies. In the present study, we have combined the analysis of a murine model and human samples of HCC to identify genes differentially expressed early in the process of hepatocarcinogenesis, using a microarray-based approach. Expression of 190 genes was impaired in murine HCC from which 65 were further validated by low-density array real-time polymerase chain reaction (RT-PCR). The expression of the best 45 genes was then investigated in human samples resulting in 18 genes in which expression was significantly modified in HCC. Among them, JUN, methionine adenosyltransferase 1A and 2A, phosphoglucomutase 1, and acyl CoA dehydrogenase short/branched chain indicate defective cell proliferation as well as one carbon pathway, glucose and fatty acid metabolism, both in HCC and cirrhotic liver, a well-known preneoplastic condition. These alterations were further confirmed in public transcriptomic datasets from other authors. In addition, vasodilator-stimulated phosphoprotein, an actin-associated protein involved in cytoskeleton remodeling, was also found to be increased in the liver and serum of cirrhotic and HCC patients. In addition to revealing the impairment of central metabolic pathways for liver homeostasis, further studies may probe the potential value of the reported genes for the early detection of HCC.