Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Persistent infections with Chlamydia pneumoniae have been implicated in the development of chronic diseases, such as atherosclerosis and asthma. Although azithromycin, clarithromycin, and levofloxacin are frequently used for the treatment of respiratory C. pneumoniae infections, little is known about the dose and duration of therapy needed to treat a putative chronic C. pneumoniae infection. In this study, we investigated the effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on the viability of C. pneumoniae and cytokine production in an in vitro model of continuous infection. We found that a 30-day treatment with azithromycin, clarithromycin, and levofloxacin at concentrations comparable to those achieved in the pulmonary epithelial lining fluid reduced but did not eliminate C. pneumoniae in continuously infected HEp-2 cells. All three antibiotics decreased levels of interleukin-6 (IL-6) and IL-8 in HEp-2 cells, but this effect appeared to be secondary to the antichlamydial activity, as the cytokine levels correlated with the concentrations of microorganisms. The levels of IL-1beta, IL-4, IL-10, tumor necrosis factor alpha, and gamma interferon were too low to assess the effect of antibiotics. These data suggest that the dosage and duration of antibiotic therapy currently being used may not be sufficient to eradicate a putative chronic C. pneumoniae infection.
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PMID:Effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on Chlamydia pneumoniae in a continuous-infection Model. 1179 50

Persistent infection with Chlamydia pneumoniae (Chlamydophila pneumoniae) has been implicated in the development of atherosclerosis, asthma and other chronic diseases. However, data on treatment of C. pneumoniae infections are limited. Microbiological failure of antimicrobial therapy has been described, even after prolonged courses of treatment with azithromycin, doxycycline and erythromycin. Gemifloxacin is an enhanced-affinity fluoroquinolone with excellent activity against most common respiratory pathogens, including C. pneumoniae. The effect of prolonged treatment with gemifloxacin, compared with azithromycin, on viability of C. pneumoniae was investigated in a continuous infection model. Gemifloxacin at final con-centrations of 0.25 and 2.5 mg/L reduced the viability of C. pneumoniae by 5 log(10), which was similar to the effect of azithromycin. However, both antimicrobials failed to completely eliminate C. pneumoniae from continuously infected cells, even after 30 days of treatment. Both antibiotics decreased levels of interleukin-6 and interleukin-8 in this model, but this effect appeared to be secondary to the antichlamydial activity, as the cytokine levels correlated with the concentrations of microorganisms.
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PMID:Effect of gemifloxacin on viability of Chlamydia pneumoniae (Chlamydophila pneumoniae) in an in vitro continuous infection model. 1200 69

Patients with nocturnal asthma demonstrate circadian variations in airway inflammation. We hypothesized that melatonin, a circadian rhythm regulator, modulates circadian inflammatory variations in asthma. The effect of melatonin stimulation on peripheral blood mononuclear cell cytokine production was evaluated at 4:00 P.M. and 4:00 A.M. in normal control subjects, patients with nocturnal asthma, and patients with non-nocturnal asthma. Melatonin was proinflammatory, causing significantly increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha at 4:00 P.M. and 4:00 A.M. in all subject groups (range, 12.8 +/- 3.3 to 131.72 +/- 16.4%, p < or = 0.0003). The observed increases in cytokine production did not change between 4:00 P.M. and 4:00 A.M. in control subjects or in patients with nocturnal asthma (p > 0.05, both cases). At 4:00 P.M., the cytokine response to melatonin of patients with nocturnal asthma was greater than that of control subjects or patients with non-nocturnal asthma and did not change significantly at 4:00 A.M. At 4:00 P.M., the cytokine response of patients with non-nocturnal asthma was less than that of patients with nocturnal asthma and rose significantly at 4:00 A.M. (p = 0.0001, all comparisons). Melatonin is proinflammatory in both patients with asthma and healthy subjects. Patients with nocturnal asthma demonstrate the largest daytime cytokine response and cannot be further stimulated at 4:00 A.M., suggesting chronic overstimulation in vivo. These results suggest differential immunomodulatory effects of melatonin based on asthma clinical phenotype and may indicate an adverse effect of exogenous melatonin in asthma.
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PMID:Immunomodulatory effects of melatonin in asthma. 1237 48

Airway fungal infections are often associated in asthmatics with the exacerbation of asthma symptoms. However, the pathomechanism of this phenomenon has not been fully understood. The aim of our study was to assess whether antimycotic treatment can influence the capacity of bronchoalveolar (BAL) leukocytes to release proinflammatory cytokines, which could contribute to increase in asthma severity. Ten patients with bronchial asthma complicated by airway fungal infections (Candida albicans and/or Aspergillus fumigatus) were included in the study. Seven asthmatics were treated with systemic and inhaled corticosteroids, whereas the remaining three with inhaled ones only. All subjects underwent several courses of therapy with antibiotics due to respiratory infections. BAL leukocytes obtained from the patients were cultured in the absence or presence of lipopolysaccharide E.coli (LPS) or Newcastle disease virus (NDV). The BAL procedure and measurement of the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (II-6), interferon-gamma (IFN-gamma), and interferon-alpha (IFN-alpha) by specific bioassays were performed twice: before antimycotic treatment and after 3 weeks of therapy with 8 mg of nebulized fluoconazole and 400 mg of oral ketoconazole per day. The elimination of fungi from respiratory tract resulted in an apparent clinical improvement. This coincided with diminished production of TNF-alpha in response to LPS and the production of IFN-alpha in response to NDV, which were initially high and subsided significantly after antimycotic therapy (p = 0.035, and 0.011, respectively). Such changes were not observed in the case of IFN-gamma and IL-6. This may suggest that TNF-alpha as well as IFN-alpha are secreted by fungi-prestimulated leukocytes from the lower respiratory tract and may be involved in the processes of exacerbation of asthma complicated by fungal infections. Further analyses of relationships between changes in cytokine levels and clinical parameters indicated that IFN-alpha seems to be of particular interest in fungal stimulation of asthma.
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PMID:Relevance of the selected cytokine release (TNF-alpha, IL-6, IFN-gamma, and IFN-alpha) to the exacerbation of bronchial asthma from airway mycotic infections. Predominant role of TFN-alpha? 1253 Jan 17

The low affinity A(2B) adenosine receptor, like any other adenosine receptor subtype, belongs to the super-family of seven transmembrane domain protein-coupled receptors (7TMs GPCR) and is classified by the GPCR database in the family of rhodopsin like receptors (Class A of GPCR). It has been cloned from various species, including rat and human, and its sequences are highly similar across species, ranging from 85% identity between human and mouse and 95% identity between rat and mouse. The A(2B)receptors show a ubiquitous distribution, the highest levels are present in cecum, colon and bladder, followed by blood vessels, lung, eye and mast cells. Through A(2B) receptors adenosine seems to cause mast cells degranulation, vasodilation, cardiac fibroblast proliferation, inhibition of Tumor Necrosis Factor (TNF-alpha), increased synthesis of interleukin-6 (IL-6), stimulation of Cl(-) secretion in intestinal epithelia and hepatic glucose production. Hence, A(2B) adenosine receptor agonists could be useful in the treatment of cardiac diseases like hypertension or myocardial infarction and in the management of septic shock, while antagonists may serve as novel drugs for asthma, Alzheimer's disease, cystic fibrosis and type-II diabetes. No potent and selective A(2B) agonists have been reported so far; 5'-N-ethylcarboxamidoadenosine (NECA) is one of the most active. The monosubstitution on N(6)-position of adenosine is well tolerated and that position appears to be a useful site for increasing A(2B) potency. Among substituents in 2-position of adenosine only 1-alkynyl chains are effective for A(2B) potency. In particular, the (S)-2-hydroxypropynyl substituents brought about the highest activity demonstrating that the A(2B) receptors discriminate between (R) and (S) diastereomers. Hence, (S)-2-phenylhydroxypropynylNECA (PHPNECA), with an EC(50) = 0.22 micro M, proved to be the most potent A(2B) agonist reported so far. Classical antagonists for adenosine receptors are alkylxanthines which show considerable potency at A(2B) receptors. Para substituted 1,3-dialkyl-8-phenylxanthines possess high affinity in binding assays; the 3-unsubstituted 1-alkyl analogues resulted more A(2B) selective with the 8-[4-[(N-(2-hydroxyethyl)carboxamidomethyl)oxy]phenyl]-1-propylxanthine (60) showing the highest affinity (K(i) = 1.2 nM) and selectivity (A(1)/A(2B) = 60, A(2A)/A(2B) = 1,790, A(3)/A(2B) = 360). Among non-xanthine derivatives very promising are substituted purines, in which combination of appropriate substituents in 2-, 8-, and 9-position could lead to very potent and selective A(2B) antagonists.
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PMID:Medicinal chemistry and pharmacology of A2B adenosine receptors. 1257 Jul 60

Adenosine (Ado) has been suggested to play a role in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. The goal of this study was to determine the effect of Ado and its receptor subtypes on cytokine release by bronchial smooth muscle cells. The A2B Ado receptor (AdoR) was expressed at the highest level among the four AdoR subtypes. Activation of the A2B AdoR by an Ado analog, 5'-(N-ethylcarboxamido)-adenosine (NECA), increased cAMP accumulation with potency (EC50 value) of 21.2 +/- 0.2 microM. The effect of NECA on the expression of the inflammatory cytokines was determined using a cDNA array consisting of 23 cytokine genes and confirmed using real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. NECA increased the release of interleukin-6 and monocyte chemotactic protein-1 proteins with EC50 values of 1.26 +/- 0.25 microM and 0.40 +/- 0.08 microM, respectively, and the maximal folds of induction were 20.8 +/- 1.7- and 6.4 +/- 0.7-fold, respectively. Selective agonists for the A1, A2A, and A3 AdoR subtypes had no effect on cytokine release. The effects of NECA were attenuated by selective antagonists of the A2B AdoR. Thus, Ado increases the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells via activation of the A2B AdoR. Our findings provide a novel mechanism whereby Ado acts as a proinflammatory mediator in the airway.
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PMID:A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells. 1285 6

The CD14-159 C --> T polymorphism, a single nucleotide polymorphism (SNP) at position -159 in the promoter region of the gene encoding the pattern recognition receptor CD14, has been associated with elevated plasma concentrations of soluble CD14, lowered serum immunoglobulin E, increased risk for myocardial infarction, and decreased risk for allergy and asthma. In the present study, the CD14-159 C --> T polymorphism has been investigated in order to determine its frequency and association with proinflammatory variables and lipid profile traits of 117 volunteers. The frequency of the CD14 promoter genotype as determined by polymerase chain reaction amplification-restriction fragment length polymorphism analysis was 35.0% (CC), 44.4% (CT), and 20.5% (TT), and the T allele frequency was 42.7%. Compared with the other genotypes, notably CC homozygotes, TT homozygotes were associated with lower total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B-100 (P < 0.01) concentrations in serum. However, no association was found between the investigated SNP and inflammatory mediators such as fibrinogen, interleukin-6, tumor necrosis factor-alpha, tissue factor, C-reactive protein, plasminogen activator inhibitor-1, leukotriene B4, or thromboxane B2. In conclusion, the CD14-159 C --> T polymorphism may be an important genetic trait, related to the ability of CD14 to bind and transport lipids, such as cholesterol.
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PMID:Association of the -159 C --> T polymorphism in the CD14 promoter with variations in serum lipoproteins in healthy subjects. 1516 25

Chlamydophila (Chlamydia) pneumoniae (C. pneumoniae) is the third most common cause of community-acquired pneumonia and is probably involved in the development of certain chronic inflammatory diseases, including atherosclerosis and adult-onset asthma. Histamine, synthesized by histidine decarboxylase (HDC) from L-histidine, plays an essential role in allergic and inflammatory processes and in cell differentiation. The effect of C. pneumoniae infection on the expression of HDC has not been examined. In the present study, normal Balb/c mice and HDC knockouts, and control mice with a CD1 background were infected intranasally with C. pneumoniae. On days 1, 3, 7, 16 and 31 after infection, the normal Balb/c mice were sacrificed and divided into three groups. In the homogenized lungs of the first group, C. pneumoniae titres were determined and demonstrated peak levels on day 7. HDC production was revealed by a Western blot assay throughout the observation period of 1-16 days, and cytokine concentrations were determined by ELISA. The interleukin-3 (IL-3) and interleukin-6 (IL-6) levels were highest on day 1 and on days 1-3, respectively; the interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels reached the maximum on day 7, but the quantity of IL-4 was still three times higher than that in the control group 16 days after infection. The lungs of the mice in the second group were processed for the in situ demonstration of HDC activity, while the lungs in the third group were stained for C. pneumoniae antigen. The HDC activity was increased predominantly in the bronchial epithelial cells, while C. pneumoniae antigens were expressed especially in the interstitial macrophages. The HDC knockout mice exhibited a higher survival rate after C. pneumoniae infection than did the control mice. These results point to a strong association between local histamine production and other inflammatory mediators and are novel in demonstrating the role of histamine in the pathomechanism of C. pneumoniae infections.
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PMID:Chlamydophila (Chlamydia) pneumoniae induces histidine decarboxylase production in the mouse lung. 1455 83

Despite the role of secreted immunoglobulin D (IgD) remains still largely unknown, previous studies have suggested that secreted IgD could induce basophils degranulation in some allergic asthma patients. In the present study we have searched direct evidence of the action of IgD on KU812 cells, generally classified as an immature basophilic cell line. We analyzed by flow cytometry the capacity of IgD, purified from IgD myeloma sera, to bind KU812 cells. Biotinylated monomeric IgD (mIgD) and biotinylated oligomeric IgD (oIgD) could bind KU812 cells. Blocking experiments with others immunoglobulin isotypes showed that KU812 cells expressed an unspecific receptor for IgD. However, oIgD but not mIgD enhances the release of interleukin-6 (IL-6) from KU812 cells. On the other hand, mIgD and oIgD failed to induce histamine release from KU812 cells or from cord blood derived basophils. Since IL-6 is known to induce basophil differentiation, we proposed that IgD could be implicated in allergic disorders by stimulating IL-6 release by prebasophil cells, then IL-6 could further induce an autocrine maturation of the cells.
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PMID:Immunoglobulin D enhances interleukin-6 release from the KU812 human prebasophil cell line. 1466 36

Epidemiologic studies have shown an increased prevalence of allergic asthma in children living in a German smelter area (Hettstedt) compared with a cohort who live in a nonindustrialized area (Zerbst). However, it is not known whether ambient particles (particulate matter(2.5) [PM(2.5)]) from these areas induce distinct lung inflammation, which might be an explanation for this difference. Therefore, 100 microg of PM(2.5) suspensions, collected simultaneously in the two areas, were instilled through a bronchoscope into contralateral lung segments of 12 healthy volunteers. PM(2.5) from both Hettstedt and Zerbst increased the number of leukocytes in the bronchoalveolar lavage performed 24 hours later. PM(2.5) from Hettstedt, but not Zerbst, induced a significant influx of monocytes (Hettstedt: 7.0% vs. Zerbst: 4.3%) without influencing the expression of surface activation markers on monocytes and alveolar macrophages. Oxidant radical generation of bronchoalveolar lavage cells and cytokine concentration (interleukin-6 and tumor necrosis factor-alpha) in bronchoalveolar lavage fluid was significantly increased after instillation of Hettstedt PM(2.5). We conclude that environmentally relevant concentrations of PM(2.5) from the smelter area induced distinct airway inflammation in healthy subjects with a selective influx of monocytes and increased generation of oxidant radicals. The higher concentration of transition metals in PM(2.5) from Hettstedt might be responsible for this increased inflammation.
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PMID:Metal-rich ambient particles (particulate matter 2.5) cause airway inflammation in healthy subjects. 1522 99


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