"Omics" Technologies and the Immune System (a) , (b).

Recent advances in genomics-based identification of gene families and gene polymorphisms associated with immune system dysfunction have answered basic questions in immunology and have begun to move forward our understanding of immune-related disease processes. In toxicology, "omic" technologies have the potential to replace or supplement current immunotoxicological screening procedures, to provide insight into potential mode or mechanisms of action, and to provide data suitable for risk assessment. The application of omic technologies to the study of the immune system also has great potential to appreciably impact the diagnosis and treatment of immune-related diseases.

Comparison of normalization methods for CodeLink Bioarray data.

Background: The quality of microarray data can seriously affect the accuracy of downstream analyses. In order to reduce variability and enhance signal reproducibility in these data, many normalization methods have been proposed and evaluated, most of which are for data obtained from cDNA microarrays and Affymetrix GeneChips. CodeLink Bioarrays are a newly emerged, single-color oligonucleotide microarray platform.

Ha-ras(val12) induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-ras(val12)-transformed cells.

Heat shock proteins (Hsps) are overexpressed in many tumors, but are downregulated in some tumors. To check for a direct effect of Ha-Ras(val12) on HSP70 transcription, we transiently expressed the oncoprotein in Rat1 fibroblasts and monitored its effect on HSP70b promoter-driven reporter gene. We show that expression of Ha-Ras(val12) induced this promoter.

Effects of aerobic training on gene expression in skeletal muscle of elderly men.

Purpose: To analyze the effect of 3 months of training on global gene expression in skeletal muscle of healthy elderly men in order to better characterize the pathways that differentiate the trained from the sedentary state.

Methods: Needle biopsies were obtained from the vastus lateralis of six healthy, sedentary, 68.0 +/- 2.

Induction of intracellular calcium elevation by Delta9-tetrahydrocannabinol in T cells involves TRPC1 channels.

We have reported previously that Delta9-tetrahydrocannabinol (Delta9-THC) treatment of resting human and murine splenic T cells robustly elevated intracellular calcium ([Ca2+]i). The objective of the present investigation was to examine the putative role of [Ca2+]i store depletion and store-operated calcium (SOC) and receptor-operated cation (ROC) channels in the mechanism by which Delta9-THC increases [Ca2+]i in the cannabinoid-2 receptor-expressing human peripheral blood-acute lymphoid leukemia (HPB-ALL) human T cell line. By using the smooth endoplasmic reticulum Ca2+-ATPase pump inhibitor, thapsigargin, and the ryanodine receptor antagonist, 8-bromo-cyclic adenosine diphosphate ribose, we demonstrate that the Delta9-THC-mediated elevation in [Ca2+]i occurs independently of [Ca2+]i store depletion.

Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis.

Rationale: Many of the interstitial lung diseases represent a diagnostic and therapeutic challenge because their clinical and even histologic features are often nonspecific. Likewise, the transcriptional signatures of most of them are unknown.

Objective: To compare the gene expression patterns from patients with idiopathic pulmonary fibrosis (IPF) hypersensitivity pneumonitis (HP), and nonspecific interstitial pneumonia (NSIP) using custom oligonucleotide microarrays.

VR1-mediated depressor effects during high-salt intake: role of anandamide.

This study was designed to test the hypothesis that increased sensitivity of blood pressure to anandamide (AEA), an endocannabinoid compound, occurs during high-salt intake, which can be blocked by a selective vanilloid receptor 1(VR1) antagonist, capsazepine (CAPZ). Intravenous administration of a metabolically stable analog, methanandamide (MethA), dose-dependently decreased mean arterial pressure (MAP) in conscious rats fed a high-sodium diet (HS) for 3 weeks but it had a minimal effect in normal sodium (NS)-treated rats. The MethA-induced decrease in MAP was significantly attenuated but not abolished by CAPZ, or a selective cannabinoid receptor 1 (CB1) antagonist, SR141716A, administered separately in HS-treated rats.

Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung.

Methods And Findings: Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients.

Analysis of microarray experiments for pulmonary fibrosis.

Microarray technology allows the investigator to examine the simultaneous expression of thousands of genes in a given cell or tissue. Such experiments that probe tens of thousands of genes produce immense amounts of information. In recent years, there has been a steady increase in the availability of tools for analysis of microarray data.

From signatures to models: understanding cancer using microarrays.

Genomics has the potential to revolutionize the diagnosis and management of cancer by offering an unprecedented comprehensive view of the molecular underpinnings of pathology. Computational analysis is essential to transform the masses of generated data into a mechanistic understanding of disease. Here we review current research aimed at uncovering the modular organization and function of transcriptional networks and responses in cancer.

Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2'-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide.

Arachidonylethanolamide (anandamide, AEA) has been identified as an endogenous ligand for cannabinoid receptors CB1 and CB2. Characterization of the direct cannabimimetic actions of anandamide has been hampered by its short duration of action and rapid degradation in in vivo and in vitro systems to arachidonic acid, a precursor in the biosynthesis of a broad range of biologically active molecules. In the present studies, we utilized 2-methylarachidonyl-(2'-fluoroethyl)amide (F-Me-AEA), an analog of anandamide resistant to enzymatic degradation, to determine whether F-Me-AEA modulated T cell function similar to that of plant-derived cannabinoids.

2-Arachidonoyl-glycerol suppresses interferon-gamma production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2.

2-Arachidonoyl-glycerol (2-AG), an endogenous ligand for cannabinoid receptor types 1 and 2 (CB1 and CB2), has previously been demonstrated to modulate immune functions including suppression of interleukin-2 expression and nuclear factor of activated T cells (NFAT) activity. The objective of the present studies was to investigate the effect of 2-AG on interferon-gamma (IFN-gamma) expression and associated upstream signaling events. Pretreatment of splenocytes with 2-AG markedly suppressed phorbol 12-myristate 13-acetate plus calcium ionophore (PMA/Io)-induced IFN-gamma secretion.

Can blood gene expression predict which patients with multiple sclerosis will respond to interferon?

Gene expression patterns from peripheral blood cells may be useful as biomarkers for monitoring MS progression and response to therapy, argue Kaminski and Achiron

Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors.

Trauma survivors show marked differences in the severity and persistence of post-traumatic stress disorder (PTSD) symptoms. Early symptoms subside in most, but persist as acute and chronic PTSD in a significant minority. The underlying molecular mechanisms or outcome predictors determining these differences are not known.

Effects of concentrated ambient particles on normal and hypersecretory airways in rats.

Epidemiological studies have reported that elevated levels of particulate air pollution in urban communities are associated with increases in attacks of asthma based on evidence from hospital admissions and emergency department visits. Principal pathologic features of chronic airway diseases, like asthma, are airway inflammation and mucous hypersecretion with excessive amounts of luminal mucus and increased numbers of mucus-secreting cells in regions of the respiratory tract that normally have few or no mucous cells (ie, mucous cell metaplasia). The overall goal of the present project was to understand the adverse effects of urban air fine particulate matter (PM2.

Increase in p21 expression independent of the p53 pathway in bleomycin-induced lung fibrosis.

Although a number of animal models have been used to study the pathogenesis of lung disease, to date few studies have looked at changed in the expression of cell cycle regulatory genes. We have studied the variation in the expression of p21, p53, p27 and PCNA in bleomycin-induced lung fibrosis using animal mouse models using immuno-histochemistry and gene-expression analysis. No difference in the p53, PCNA and p27 expressions were observed from the bleomycin-induced fibrosis when compared to saline-induced non-fibrotic lungs.

Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease.

To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from COPD and control smokers. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.

Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus.

Autoimmune diseases are either tissue-specific like multiple sclerosis (MS) or multisystemic like systemic lupus erythematosus (SLE), although clinically both exhibit common features. To gain insight into the properties of the genes involved in each disease we have investigated the gene expression signature of peripheral blood mononuclear cells (PBMC) in MS and SLE in comparison to healthy subjects. Total RNA was purified, hybridized to Genechip array and analysed in 36 subjects (13 relapsing-remitting MS patients, five SLE patients and 18 age-matched healthy subjects that served as controls).

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces suppressor of cytokine signaling 2 in murine B cells.

The B cell, a major component of humoral immunity, is a sensitive target for the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), possibly by rendering cells less responsive to antigenic or mitogenic stimulation. Potential mechanisms of TCDD action on B cells were examined in murine B cell lymphoma cells (CH12.LX) treated with 3 nM TCDD or dimethyl sulfoxide vehicle using sequence-verified cDNA microarrays.

A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes.

Arachidonyl ethanolamine, which is commonly known as anandamide, was the first endogenous compound to be identified that binds to the cannabinoid receptors. Anandamide mimics many of the physiological effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), including hypothermia, antinociception, immobility, catalepsy, and immune modulation. In the present studies, we show that anandamide caused a concentration-dependent inhibition of interleukin-2 in primary splenocytes.

Interactions at a dioxin responsive element (DRE) and an overlapping kappaB site within the hs4 domain of the 3'alpha immunoglobulin heavy chain enhancer.

Our previous results describing the CH12.LX (AhR-expressing) and BCL-1 (AhR-deficient) B cell lines have supported an AhR/dioxin-responsive element (DRE)-mediated mechanism for TCDD-induced inhibition of micro heavy chain expression and thus of IgM secretion. Transcriptional regulation of the Ig heavy chain genes involves several regulatory elements including the 3'alpha Ig heavy chain enhancer, which is composed of four regulatory domains that span approximately 40 kb.

Gene expression profiling of in vivo UVB-irradiated human epidermis.

Background: Several recent studies have employed microarray profiling to study UVB-regulated gene expression in human skin. These studies are all based on UV-irradiated cultured cells that differ substantially from the intact tissues they are supposed to imitate. The purpose of the present study was to analyze the differential expression of UVB-regulated genes in intact human epidermis following in vivo UV irradiation.