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

Respiratory epithelial cells play important roles not only in host defense mechanisms, but also in inflammatory responses. Inhaled corticosteroids are widely used for the treatment of patients with inflammatory lung disorders, including asthma, chronic obstructive pulmonary disease, and sarcoidosis. Corticosteroids effectively reduce the production of inflammatory mediators, such as cytokines and chemokines. Although these molecules are also essential for host defense responses, there is no convincing evidence that inhaled corticosteroids increase susceptibility to lower respiratory tract infections. To test the involvement of Toll-like receptor (TLR) family molecules in this phenomenon, we examined the effects of various cytokines and corticosteroid on the expression of TLRs in human respiratory epithelial cells. Among the TLRs tested, TLR2 expression was significantly enhanced after stimulation with a combination of tumor necrosis factor-alpha and interferon-gamma. Dexamethasone synergistically enhanced TLR2 expression in combination with tumor necrosis factor-alpha and interferon-gamma in terms of both mRNA and protein levels. Furthermore, increased cell-surface TLR2 was functional, judging from the remarkable induction of interleukin-6, interleukin-8, and beta-defensin-2 after stimulation with peptidoglycan. These results provide evidence for a novel function of corticosteroids in airway inflammatory disorders, and indicate that the use of inhaled corticosteroids in such disorders may have a beneficial role in host defense mechanisms.
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PMID:Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells. 1524 47

Recent evidence suggests that CD38, an ectoenzyme that converts NAD(+) to cyclic ADP-ribose (cADPr), may play a role in cytokine-induced airway smooth muscle (ASM) cell hyper-responsiveness, a key feature associated with chronic asthma. In the present study, we investigated the major signaling pathways by which tumor necrosis factor-alpha (TNFalpha) induces CD38 expression and its role in regulating gene expression in human ASM cells. Using flow cytometry analyses, TNFalpha enhanced CD38 expression in a manner that was time-(0-24 h), concentration-(0.1-40 ng/ml), and protein synthesis-(cycloheximide blockade) dependent. A selective agonistic antibody against tumor necrosis factor receptor (TNFR) 1 also augmented CD38 expression, whereas anti-TNFR2 antagonistic antibody did not prevent the TNFalpha response. Inhibition of the Janus activated kinase/signal transducer and activator of transcription pathways using the soluble inhibitor 2-(1,1-dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz-[h]imidaz[4,5-f]isoquinolin-7-one (DBI) or with neutralizing antibody against interferon beta (IFNbeta) completely abrogated TNFalpha-induced CD38 expression at both protein and mRNA levels. Combining TNFalpha (0.1 and 1 ng/ml) and IFNbeta (100 IU/ml) at concentrations alone that had little effect on CD38 expression induced a robust synergistic induction of CD38 mRNA and protein levels. 8-Bromo-cADPr, a cADPr antagonist, significantly augmented TNFalpha-induced interleukin-6 secretion, whereas regulated on activation normal T cell expressed and secreted secretion was suppressed. 8-Bromo-cADPr, however, did not affect TNFalpha-induced cell surface expression of intercellular adhesion molecule-1. Our study is the first to demonstrate that IFNbeta-dependent activation of CD38 pathway is a novel component by which TNFalpha differentially regulates the expression of inflammatory genes in ASM cells.
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PMID:Tumor necrosis factor-alpha differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-beta-dependent CD38 pathway. 1526 23

The inflammatory response to ozone in atopic asthma suggests that soluble mediators of inflammation are released in response to oxidant stress. Antioxidants may alleviate additional oxidative stress associated with photochemical oxidant pollution. This study investigates the impact of antioxidant supplementation on the nasal inflammatory response to ozone exposure in atopic asthmatic children. We conducted a randomized trial using a double-blinded design. Children with asthma (n = 117), residents of Mexico City, were given randomly a daily supplement of vitamins (50 mg/day of vitamin E and 250 mg/day of vitamin C) or placebo. Nasal lavages were performed three times during the 4-month follow-up and analysed for content of interleukin-6 (IL-6), IL-8, uric acid and glutathione (GSx). IL-6 levels in the nasal lavage were increased significantly in the placebo group after ozone exposure while no increase was observed in the supplement group. The difference in response to ozone exposure between the two groups was significant (P = 0.02). Results were similar for IL-8, but with no significant difference between the groups (P = 0.12). GSx decreased significantly in both groups. Uric acid decreased slightly in the placebo group. Our data suggest that vitamin C and E supplementation above the minimum dietary requirement in asthmatic children with a low intake of vitamin E might provide some protection against the nasal acute inflammatory response to ozone.
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PMID:Antioxidant supplementation and nasal inflammatory responses among young asthmatics exposed to high levels of ozone. 1549 43

Although chronic inhalation of endotoxin or lipopolysaccharide (LPS) causes all of the classic features of asthma, including airway hyperreactivity, airway inflammation, and airway remodeling, the mechanisms involved in this process are not clearly understood. The objective of this study was to determine whether intratracheal treatment with LPS antagonist (E5564, a lipid A analog) prevented the development of chronic endotoxin-induced airway disease in a mouse model of environmental airway disease. Pretreatment with 10 and 100 microg of E5564 was found to inhibit the airway response (hyperreactivity and inflammation) for up to 48 h after the administration of the compound. Repeated dosing with 50 microg of E5564 intratracheally did not cause any measurable toxicity. Therefore, in a chronic experiment, mice were treated with either E5564 (50 microg) or vehicle three times weekly for 5 wk and simultaneously daily exposed to either LPS (4.65 +/- 0.30 microg/m3) or saline aerosol. E5564 was effective in decreasing the airway hyperreactivity to methacholine, the air space neutrophilia, the interleukin-6 in the lung lavage fluid, and the neutrophil infiltration of the airways 36 h after 5 wk of LPS inhalation. Less collagen deposition was observed in the airways of E5564-treated mice compared with vehicle-treated mice after a 4-wk recovery period. Our results indicate that E5564, a Toll-like receptor 4 antagonist, minimizes the physiological and biological effects of chronic LPS inhalation, suggesting a therapeutic role for competitive LPS antagonists in preventing or reducing endotoxin-induced environmental airway disease.
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PMID:Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide. 1583 64

Mast cells are critical players in allergic reactions, but they have also been shown to be important in immunity and recently also in inflammatory diseases, especially asthma. Migraines are episodic, typically unilateral, throbbing headaches that occur more frequently in patients with allergy and asthma implying involvement of meningeal and/or brain mast cells. These mast cells are located perivascularly, in close association with neurons especially in the dura, where they can be activated following trigeminal nerve, as well as cervical or sphenopalatine ganglion stimulation. Neuropeptides such as calcitonin gene-related peptide (CGRP), hemokinin A, neurotensin (NT), pituitary adenylate cyclase activating peptide (PACAP), and substance P (SP) activate mast cells leading to secretion of vasoactive, pro-inflammatory, and neurosensitizing mediators, thereby contributing to migraine pathogenesis. Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines. A better understanding of brain mast cell activation in migraines would be useful and could lead to several points of prophylactic intervention.
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PMID:The role of mast cells in migraine pathophysiology. 1596 Sep 87

It is still uncertain how viral respiratory infections cause acute exacerbations of bronchial asthma, although several mechanisms have been proposed. We studied the relationship between the airway narrowing and the inflammatory and bronchospastic factors in peripheral venous blood and urine, in 30 patients with asthma at the exacerbations caused by upper respiratory tract infections (URTIs). Acute exacerbations caused decreases in peak expiratory flow rate (PEFR) in all 30 patients with asthma. Asthma exacerbations caused the rises in serum levels of interleukin-6, soluble intercellular adhesion molecule-1 and eosinophil cationic protein, concentrations of urinary leukotriene E4 and plasma histamine, compared with those in patients with asthma at a stable condition and those in 30 control subjects (p < 0.05). The values of PEFR at the exacerbations correlated with the levels of these factors. Treatment with oral glucocorticoids reversed the decreases in PEFR and the increases in these factors. At the onset of URTIs, rhinovirus and influenza type A virus were identified in 13 and 7 patients, respectively. Each of parainfluenza virus, adenovirus, and enterovirus was identified in one patient. These findings suggest that respiratory viral infections may cause acute asthma exacerbations via the production of mediators that induce inflammation and bronchospasm.
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PMID:Inflammatory and bronchospastic factors in asthma exacerbations caused by upper respiratory tract infections. 1614 79

Rhinoviruses (RV) are the major cause of the common cold and acute exacerbations of asthma and chronic obstructive pulmonary disease. Toll-like receptors (TLRs) are a conserved family of receptors that recognize and respond to a variety of pathogen-associated molecular patterns. TLR3 recognizes double-stranded RNA, an important intermediate of many viral life cycles (including RV). The importance of TLR3 in host responses to virus infection is not known. Using BEAS-2B (a human bronchial epithelial cell-line), we demonstrated that RV replication increased the expression of TLR3 mRNA and TLR3 protein on the cell surface. We observed that blocking TLR3 led to a decrease in interleukin-6, CXCL8, and CCL5 in response to poly(IC) but an increase following RV infection. Finally, we demonstrated that TLR3 mediated the antiviral response. This study demonstrates an important functional requirement for TLR3 in the host response against live virus infection and indicates that poly(IC) is not always a good model for studying the biology of live virus infection.
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PMID:Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. 1616 Jan 53

Recent evidence suggests that inflammatory pathways are important mediators of carcinogenesis. Asthma, allergic rhinitis and atopic dermatitis are clinical manifestations of a systemic atopic disorder, which is associated with airway hyper-responsiveness and inflammation. We examined the effect of a history of asthma/atopy among 132 lung cancer cases (of which 72% were adenocarcinomas) and 163 controls, all of whom were non-smoking Chinese women, in combination with a single nucleotide polymorphism (-634C/G) in the interleukin-6 (IL-6) gene which regulates secretion of a pro-inflammatory cytokine found to be predominant in lung tumour tissue. We observed a slight increase in risk of lung cancer [odds ratio, OR = 1.5, 95% confidence interval (95% CI) = 0.8-2.6] and of adenocarcinoma (OR = 1.6, 95% CI = 0.9-3.1) with asthma/atopy alone. There was no effect of the IL-6 CG/GG genotype on lung cancer risk on its own. Among individuals with both asthma/atopy and the IL-6 -634 G allele, however, risk was increased at least 3-fold (OR = 3.1, 95% CI = 1.2-8.3 for all cancers and OR = 4.2, 95% CI = 1.5-11.6 for adenocarcinomas) relative to individuals with no asthma/atopy and the CC genotype. On stratified analysis, a significant increase in risk with asthma/atopy was restricted to those with the at-risk genotype (Pint < 0.05). Our findings are consistent with the role of chronic inflammation as an aetiologic factor among non-smoking Asian women, and suggest that asthma/atopy is a risk marker for susceptibility to the development of lung cancer.
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PMID:Joint effect of asthma/atopy and an IL-6 gene polymorphism on lung cancer risk among lifetime non-smoking Chinese women. 1634 68

Interleukin-6 (IL-6) is a cytokine, which plays an important role in many chronic inflammatory diseases. IL-6 belongs to a family of 10 cytokines, which all act via receptor complexes containing the cytokine receptor subunit gp130. On cells, IL-6 first binds to a specific membrane-bound IL-6R and the complex of IL-6 and IL-6R interacts with gp130 leading to signal initiation. Whereas gp130 is widely expressed throughout the body, the IL-6R is only found on some cells including hepatocytes and some leucocytes. A soluble form of the IL-6R is an agonist capable of transmitting signals through interaction with the gp130 protein. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells, which are unresponsive to IL-6 alone, as they do not express the membrane-bound IL-6R. We have named this process trans-signalling. We provided evidence that a soluble form of the IL-6 family signalling receptor subunit gp130 is the natural inhibitor of IL-6 trans-signalling responses. We showed that in chronic inflammatory diseases such as inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma as well as in colon cancer, IL-6 trans-signalling is critically involved in the maintenance of the disease state. Moreover, in all these animal models, the progression of the disease can be interrupted by specifically interfering with IL-6 trans-signalling using recombinant-soluble gp130Fc protein. The pathophysiologic mechanisms by which the IL-6/soluble IL-6R complex perpetuates the inflammatory state are discussed.
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PMID:Interleukin-6 trans-signalling in chronic inflammation and cancer. 1664 Jun 55

The immediate-type allergic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. The discovery of drugs for the treatment of immediate-type allergic diseases is a very important subject in human health. In this study, we investigated the effect of Artemisia iwayomogi (AIAE) on mast cell-mediated allergic reaction and inflammatory cytokine secretion. AIAE inhibited compound 48/80-induced systemic reactions in mice. AIAE decreased the passive cutaneous anaphylaxis (PCA) reaction activated by antidinitrophenyl (anti-DNP) IgE antibody. AIAE dose-dependently reduced histamine release from rat peritoneal mast cells activated by compound 48/80 or anti-DNP IgE. Furthermore, AIAE attenuated the phorbol 12-myristate 13-acetate plus calcium ionophore A23187-stimulated tumor necrosis factor-alpha and interleukin-6 secretion in human mast cells. These results provide evidence that AIAE may be beneficial in the treatment of allergic diseases.
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PMID:Artemisia iwayomogi inhibits immediate-type allergic reaction and inflammatory cytokine secretion. 1699 91


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