Sarcoidosis is an inflammatory granulomatous disease with unknown etiology driven by cytokines and chemokines. There is limited information regarding the regulation of cytokine/chemokine-receptor network in bronchoalveolar lavage (BAL) cells in pulmonary sarcoidosis, suggesting contribution of miRNAs and transcription factors. We therefore investigated gene expression of 25 inflammation-related miRNAs, 27 cytokines/chemokines/receptors, and a Th1-transcription factor T-bet in unseparated BAL cells obtained from 48 sarcoidosis patients and 14 control subjects using quantitative RT-PCR. We then examined both miRNA-mRNA expressions to enrich relevant relationships. This first study on miRNAs in sarcoid BAL cells detected deregulation of miR-146a, miR-150, miR-202, miR-204, and miR-222 expression comparing to controls. Subanalysis revealed higher number of miR-155, let-7c transcripts in progressing (n = 20) comparing to regressing (n = 28) disease as assessed by 2-year follow-up. Correlation network analysis revealed relationships between microRNAs, transcription factor T-bet, and deregulated cytokine/chemokine-receptor network in sarcoid BAL cells. Furthermore, T-bet showed more pronounced regulatory capability to sarcoidosis-associated cytokines/chemokines/receptors than miRNAs, which may function rather as "fine-tuners" of cytokine/chemokine expression. Our correlation network study implies contribution of both microRNAs and Th1-transcription factor T-bet to the regulation of cytokine/chemokine-receptor network in BAL cells in sarcoidosis. Functional studies are needed to confirm biological relevance of the obtained relationships.
- MeSH
- dospělí MeSH
- genové regulační sítě * MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA analýza MeSH
- mikro RNA fyziologie MeSH
- plicní sarkoidóza imunologie MeSH
- proteiny T-boxu fyziologie MeSH
- receptory chemokinů genetika MeSH
- receptory cytokinové genetika MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Monocytes play an essential role in the defense against bacterial pathogens. Bone marrow (BM) and peripheral blood (PB) monocytes in pigs consist of the main "steady-state" subpopulations: CD14 hi/CD163-/SLA-DR- and CD14 low/CD163+/SLA-DR+. During inflammation, the subpopulation of "inflammatory" monocytes expressing very high levels of CD163, but lacking the SLA-DR molecule (being CD14 low/CD163+/SLA-DR-) appears in the BM and PB and replaces the CD14 low/CD163+/SLA-DR+ subpopulation. However, current knowledge of monocyte migration into inflamed tissues in pigs is limited. The aim of the present study was to evaluate the distribution of "inflammatory" CD14 low/CD163+/SLA-DR- monocytes during experimental inflammation induced by Actinobacillus pleuropneumoniae (APP) and a possible role for chemokines in attracting "inflammatory" CD14 low/CD163+/SLA-DR- monocytes into the tissues. Monocyte subpopulations were detected by flow cytometry. Chemokines and chemokine receptors were detected by RT-qPCR. The "steady-state" monocytes were found in the BM, PB, spleen and lungs of control pigs. After APP-infection, "inflammatory" monocytes replaced the "steady-state" subpopulation in BM, PB, spleen and moreover, they appeared in an unaffected area, demarcation zone and necrotic area of the lungs and in tracheobronchial lymph nodes. They did not appear in mesenteric lymph nodes. Levels of mRNA for various chemokines with their appropriate receptors were found to be elevated in BM (CCL3-CCR1/CCR5, CCL8-CCR2/CCR5, CCL19-CCR7), necrotic area of the lungs (CCL3-CCR1, CCL5-CCR1/CCR3, CCL11-CCR3, CCL22/CCR4) and tracheobronchial lymph nodes (CCL3-CCR1) and therefore they could play a role in attracting monocytes into inflamed tissues. In conclusion, "inflammatory" monocytes appear in different lymphoid tissues and the lungs after APP infection in pigs. Various chemokines could drive this process.
- MeSH
- Actinobacillus pleuropneumoniae fyziologie MeSH
- antigeny diferenciační myelomonocytární metabolismus MeSH
- CD antigeny metabolismus MeSH
- chemokiny genetika metabolismus MeSH
- infekce bakteriemi rodu Actinobacillus imunologie mikrobiologie veterinární MeSH
- lymfoidní tkáň metabolismus MeSH
- messenger RNA genetika MeSH
- monocyty cytologie metabolismus MeSH
- nemoci prasat imunologie mikrobiologie MeSH
- plíce metabolismus MeSH
- prasata MeSH
- průtoková cytometrie veterinární MeSH
- receptory buněčného povrchu metabolismus MeSH
- receptory chemokinů genetika metabolismus MeSH
- zánět mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with "sarcoidosis-associated" genes. Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry. Patient's BAL cells expressed higher mRNA T-bet levels than those of controls (mean ± sd fold change 3.64 ± 1.72; p = 0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p > 0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor β, CXCR3 and CXCR6 (p < 0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes. In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.
- MeSH
- bronchoalveolární lavážní tekutina chemie cytologie MeSH
- chemokin CCL5 genetika metabolismus MeSH
- dospělí MeSH
- exprese genu MeSH
- interferon gama genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické uzliny metabolismus MeSH
- messenger RNA metabolismus MeSH
- plíce metabolismus MeSH
- plicní sarkoidóza genetika imunologie metabolismus MeSH
- proteiny T-boxu metabolismus MeSH
- receptory chemokinů genetika metabolismus MeSH
- receptory CXCR3 genetika metabolismus MeSH
- receptory interleukinu-2 genetika metabolismus MeSH
- Th1 buňky imunologie metabolismus MeSH
- upregulace MeSH
- virové receptory genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
CONTEXT: Low-grade inflammation links obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. OBJECTIVE: To explore the expression profile of genes involved in inflammatory pathways in adipose tissue and peripheral monocytes (PM) of obese patients with and without T2DM at baseline and after dietary intervention. DESIGN: Two-week intervention study with very-low-calorie diet (VLCD). SETTING: University hospital. Patients: Twelve obese females with T2DM, 8 obese nondiabetic females (OB) and 15 healthy age-matched females. INTERVENTION: Two weeks of VLCD (2500 kJ/d). MAIN OUTCOME MEASURES: Metabolic parameters, circulating cytokines, hormones, and mRNA expression of 39 genes in sc adipose tissue (SCAT) and PM. RESULTS: Both T2DM and OB group had significantly increased serum concentrations of circulating proinflammatory factors (C-reactive protein, TNFα, IL-6, IL-8), mRNA expression of macrophage antigen CD68 and proinflammatory chemokines (CCL-2, -3, -7, -8, -17, -22) in SCAT and complementary chemokine receptors (CCR-1, -2, -3, -5) and other proinflammatory receptors (toll-like receptor 2 and 4, TNF receptor superfamily 1A and 1B, IL-6R) in PM, with OB group showing less pronounced chemoattracting and proinflammatory profile compared to T2DM group. In T2DM patients VLCD decreased body weight, improved metabolic profile, and decreased mRNA expression of up-regulated CCRs in PM and chemokines [CCL 8, chemokine (C-X-C motif) ligand 10] in SCAT. VLCD markedly increased mRNA expression of T-lymphocyte attracting chemokine CCL-17 in SCAT. CONCLUSION: Obese patients with and without T2DM have increased mRNA expression of chemotactic and proinflammatory factors in SCAT and expression of corresponding receptors in PM. Two weeks of VLCD significantly improved this profile in T2DM patients.
- MeSH
- adipokiny genetika metabolismus MeSH
- chemokiny genetika metabolismus MeSH
- diabetes mellitus 2. typu krev komplikace dietoterapie genetika MeSH
- kalorická restrikce MeSH
- lidé středního věku MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- messenger RNA genetika metabolismus MeSH
- monocyty metabolismus MeSH
- obezita krev komplikace dietoterapie genetika MeSH
- podkožní tuk metabolismus MeSH
- receptory adipokinů genetika metabolismus MeSH
- receptory chemokinů genetika metabolismus MeSH
- redukční dieta MeSH
- regulace genové exprese MeSH
- zánět komplikace genetika metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky kontrolované MeSH
- práce podpořená grantem MeSH
Differences in biological responses to exposure to hazardous airborne substances between children and adults have been reported, suggesting children to be more susceptible. Aim of this study was to improve our understanding of differences in susceptibility in cancer risk associated with air pollution by comparing genome-wide gene expression profiles in peripheral blood of children and their parents. Gene expression analysis was performed in blood from children and parents living in two different regions in the Czech Republic with different levels of air pollution. Data were analyzed by two different approaches: one method first selected significantly differentially expressed genes and analyzed these gene lists for overrepresented biological processes, whereas the other applied the T-profiler tool to directly perform pathway analyses on the total gene set without preselection of significantly modulated gene expressions. In addition, gene expressions in both children and adults were investigated for associations with micronuclei frequencies. Both analysis approaches returned considerably more genes or gene groups and pathways that significantly differed between children from both regions than between parents. Very little overlap was observed between children and adults. The two most important biological processes or molecular functions significantly modulated in children, but not in adults, are nucleosome and immune response related. Our study suggests differences between children and adults in relation to air pollution exposure at the transcriptome level. The findings underline the necessity of implementing environmental health policy measures specifically for protecting children's health.
- MeSH
- dítě MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- nukleární rodina MeSH
- receptory chemokinů genetika MeSH
- regulace genové exprese MeSH
- RNA genetika MeSH
- rodiče MeSH
- sestřih RNA genetika MeSH
- stanovení celkové genové exprese * MeSH
- znečištění ovzduší * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
OBJECTIVE: CCX CKR is a decoy chemokine receptor that specifically binds the chemokines CCL19, CCL25 and CCL21. CCL19 was previously found to be upregulated in pulmonary sarcoidosis. We have, therefore, investigated CCX CKR expression in this inflammatory disease. METHODS AND RESULTS: CCX CKR mRNA was semiquantitated using RT-PCR in unseparated bronchoalveolar (BAL) cells from sarcoidosis patients (S, n = 29) and healthy control subjects (C, n = 9). CCX CKR transcripts were upregulated in patients (mean +/- SEM); S, 0.82 +/- 0.10; C, 0.44 +/- 0.04; p = 0.01; this upregulation paralleled the disease course as assessed by the chest radiographic stage (p < 0.02). Immunocytochemistry localised the CCX CKR protein to ciliated bronchial cells. Flow cytometric fluorescent ligand uptake assay showed that these cells are able to internalize its ligand. CONCLUSION: These observations implicate CCX CKR in the modulation of the inflammatory response in sarcoidosis.
- MeSH
- bronchoalveolární lavážní tekutina * cytologie chemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA biosyntéza MeSH
- plicní sarkoidóza imunologie metabolismus MeSH
- počet leukocytů MeSH
- receptory CCR MeSH
- receptory chemokinů * biosyntéza genetika MeSH
- upregulace MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- dospělí MeSH
- finanční podpora výzkumu jako téma MeSH
- hodnocení rizik MeSH
- infarkt myokardu genetika MeSH
- lidé MeSH
- nemoci koronárních tepen genetika MeSH
- polymerázová řetězová reakce MeSH
- polymorfismus genetický MeSH
- populační charakteristiky MeSH
- receptory chemokinů genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Chemokines mediate their multiple effects by binding to a variety of specific receptors, that comprise a subfamily of rhodopsin-like, 7-transmembrane domain receptors, coupled to G proteins. Some of these receptors serve as coreceptors for HIV, some of them could be expressed as markers for T lymphocyte functional differentiation. This review aims at summarising data on chemokine receptors, their function in vivo, their target cells and it also mentions association of chemokine receptor polymorphisms with human disease.
- MeSH
- buněčná diferenciace fyziologie MeSH
- lidé MeSH
- ligandy MeSH
- myši knockoutované genetika MeSH
- myši MeSH
- polymorfismus genetický MeSH
- receptory chemokinů genetika metabolismus fyziologie MeSH
- T-lymfocyty cytologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH