Association Between IL-1 β /TNF- α –Induced Glucocorticoid-Sensitive Changes in Multiple Gene Expression and Altered Responsiveness in Airway Smooth Muscle

Hákonarson, Hákon; Halapi, Eva; Whelan, Russell S.; Gulcher, Jeffrey R.; Stefánsson, Kári; Grunstein, Michael

doi:10.1165/ajrcmb.25.6.4628

Cited by 77 publications

(61 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ours is the first report to show that ET-1 induces CCN2 and, thus, that CCN2 could also be a downstream mediator of ET-1 activity. The ET-1 response element of the CCN2 promoter is independent of its Smad element, which is required for the TGF␤-induction of CCN2 (22,47). Instead, the ET-1 induction of CCN2 occurs through the BCE-1 element of the CCN2 promoter, which is not required for the TGF␤-induction of CCN2 (22).…”

Section: Discussionmentioning

confidence: 99%

“…CCN2 is a cysteine-rich, pro-adhesive, matricellular protein that plays an essential role in the formation of blood vessels, bone, and connective tissue (46). Because the expression of this protein is potently induced by TGF␤ in a Smad-dependent fashion (22), it has been hypothesized that CCN2 mediates several of the downstream actions of TGF␤ (26). Ours is the first report to show that ET-1 induces CCN2 and, thus, that CCN2 could also be a downstream mediator of ET-1 activity.…”

Section: Discussionmentioning

confidence: 99%

“…The ET-1 response element of the CCN2 promoter is independent of its Smad element, which is required for the TGF␤-induction of CCN2 (22,47). Instead, the ET-1 induction of CCN2 occurs through the BCE-1 element of the CCN2 promoter, which is not required for the TGF␤-induction of CCN2 (22). These results suggest that TGF␤ and ET-1 might work Ϫ805, a construct containing nucleotides Ϫ805 to ϩ 17 of the CCN2 promoter; Ϫ244, a construct containing nucleotides Ϫ244 to ϩ17 of the CCN2 promoter; Ϫ86, a construct containing nucleotides Ϫ86 to ϩ17 of the CCN2 promoter; Ϫ805 Smad, a construct containing a mutation in the Smad binding element of the CCN2 promoter; Ϫ805 BCE-1, a construct containing a mutation in the BCE-1 binding element of the CCN2 promoter.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Endothelin-1 Induces Expression of Matrix-associated Genes in Lung Fibroblasts through MEK/ERK

Howat

Renzoni

et al. 2004

Journal of Biological Chemistry

150

View full text Add to dashboard Cite

The endothelins are a family of endothelium-derived peptides that possess a variety of biological activities, including potent vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and pulmonary fibrosis. Here, we use genome-wide expression array analysis to show that the addition of ET-1 (100 nM, 4 h) to normal lung fibroblasts directly induces expression of matrix and matrix-associated genes, including the profibrotic protein CCN2 (connective tissue growth factor, or CTGF). ET-1 induces the MEK/ERK MAP kinase pathway in fibroblasts. Blockade of the MEK/ERK kinase pathway with U0126 abrogates the ability of ET-1 to induce expression of matrix and matrix-associated mRNAs and the CCN2 protein. The CCN2 promoter possesses an ET-1 response element, which maps to the previously identified basal control element-1 (BCE-1) site. Our results suggest that ET-1 induces a program of matrix synthesis in lung fibroblasts and that ET-1 may play a key role in connective tissue deposition during wound repair and in pulmonary fibrosis.As a response to environmental insults or a consequence of local inflammatory processes, structural damage to tissue can occur, triggering a wound-healing response. This response consists of an integrated series of biochemical, immunological, and structural changes that result in the de novo synthesis of a new epithelium, blood vessels, and connective tissue (1). The proper repair of connective tissue requires the synthesis and organization of new ECM 1 components, such as collagen and fibronectin (2).A growing body of evidence implicates the vasoconstrictive peptide endothelin-1 (ET-1) as a key mediator of tissue repair (3). Each of the three known endothelin isoforms (-1, -2, and -3) arise by proteolytic processing of large precursors (ϳ200 amino acid residues). Intermediates, termed big ET-1, -2, and -3 (38 -41 amino acids), are excised from pre-propeptides at sites containing paired basic amino acids. Big endothelins, which have little or no biological activity (4), are cleaved at Trp-21-Val/Ile-22 to produce mature, 21-residue, biologically active peptides (5, 6). The enzyme responsible for the specific cleavage at Trp-21 has been termed the endothelin-converting enzyme (7,8). Injury and the wound-healing response lead to stabilization of endothelin-converting enzyme-1 mRNA and to the generation of bioactive endothelin (9). Elevated levels of ET-1 have been shown in patients with fibrotic disease, suggesting that ET-1 may play a key role not only in normal wound repair but also in the pathogenesis of fibrosis (10 -14).ET-1 demonstrates a wide range of biological properties, including significant mitogenic activity toward a number of cell types such as smooth muscle cells and fibroblasts (15). ET-1 also promotes the contractile ability of normal fibroblasts (16), which is essential for wound closure and reconstitution of the dermis (17). In addition, ET-1 modifies extracellular matrix metabolism (15, 18 -20). For example, ET-1 enhances collagen types I and III and decreases...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Endothelin-1 Induces Expression of Matrix-associated Genes in Lung Fibroblasts through MEK/ERK

Howat

Renzoni

et al. 2004

Journal of Biological Chemistry

150

View full text Add to dashboard Cite

show abstract

“…The rationale for using this strategy is based on two well established concepts. First, the manifestations of asthma are, at least in part, channeled through the actions of IL-1␤ and TNF-␣ (11,12). Second, the efficacy of GCs in asthma is, at least in part, through its effect on the expression of genes that are modulated by proinflammatory cytokines (12,13).…”

mentioning

confidence: 99%

Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients

Hákonarson

Björnsdóttir

Halapi

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

150

105

View full text Add to dashboard Cite

Gene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n ‫؍‬ 64) and GC-resistant (n ‫؍‬ 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1␤ and TNF-␣ combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1␤͞TNF-␣ treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n ‫؍‬ 26) from the nonresponders (n ‫؍‬ 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.

show abstract

“…Glucocorticoids have bronchoprotective action to directly alter bronchial smooth muscle function by the following effects; 1) inhibition of bronchial smooth muscle contractility, 2) augmentation of bronchial smooth muscle relaxation, 3) suppression of bronchial smooth muscle proliferation, 4) prevention of the release of various cytokines and chemokines from stimulated bronchial smooth muscle, and other actions. 13,14,25) We previously reported that glucocorticoids might inhibit the AHR by reducing the protein expression and activation of a monometric GTP-binding protein, RhoA, which is involved in the agonist-induced Ca 2ϩ sensitization of bronchial smooth muscle contraction. 22 of inhibitory effect of glucocorticoid on the upregulation of RhoA induced by antigen-challenge.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Inhibitory Effect of Prednisolone on RhoA Upregulation in Human Bronchial Smooth Muscle Cells

Goto

Chiba

Sakai

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Airway hyperresponsiveness (AHR) associated with hightened airway resistance and inflammation is an asthmatic characteristic feature. Although the importance of AHR in the pathogenesis of asthma has been suggested by its relevance to the severity of this disease, the pathophysiologic alterations leading to the hyperresponsiveness are still unclear. It has been demonstrated that smooth muscle responsiveness to contractile agonists was significantly increased in bronchial preparations from repeatedly antigen challenged rats. 1) Smooth muscle contraction is mainly regulated by an increase in cytosolic Ca 2ϩ concentration in myocytes. Recently, additional mechanism, termed Ca 2ϩ sensitization, has also been suggested to be involved in the agonist-induced smooth muscle contraction. It has been demonstrated that agonist stimulation increases myofilament Ca 2ϩ sensitivity in permeabilized smooth muscles of the rat coronary artery, 2) guinea pig vas deferens, 3) canine trachea, 4) and rat bronchus. 5) Although the detailed mechanism is not fully cleared, an involvement of RhoA, a monomeric GTP-binding protein, in agonist-induced Ca 2ϩ sensitization has been suggested by many investigators. 6) Previously, we demonstrated that the Ca 2ϩ sensitization of the bronchial smooth muscle (BSM) contraction was markedly augmented concomitantly with an increased expression of RhoA protein in the AHR rats and mice. 7,8) Moreover, an augmented RhoA-mediated Ca 2ϩ sensitization of smooth muscle contraction has been reported in experimental animal models of diseases. 9,10) It is thus possible that RhoA-mediated signaling is a crucial key for understanding the abnormal contraction of diseased smooth muscles. Recent studies revealed that the RhoA upregulation is triggered by interleukin (IL)-13 and tumor necrosis factor (TNF)-a, both of which are known as major mediators for development of AHR, via activation of signal transducers and activators of transcription (STAT6) and nuclear factor (NF)-kB in human BSM cells (hBSMCs). 7,11) Glucocorticoids are by far the most effective anti-inflammatory treatment for bronchial asthma and have now become the first-line therapy in all patients with persistent asthma. The predominant effect of glucocorticoids such as prednisolone and beclomethasone is to switch off multiple inflammatory genes that have been activated during the inflammatory process. They have additional effects such as the synthesis of anti-inflammatory proteins and post-genomic effects. Recent studies have also demonstrated that glucocorticoids may affect diverse functions via glucocorticoid receptor (GR), such as an increase in b 2 receptor expression in airway smooth muscle cells, 12) decreases in chemokines and cytokines secretion in airway epithelial cells 13,14) and so on. One mechanism by which GR influences gene expression is by direct physical association with other transcription factor, such as STAT6 and NF-kB to modulate their function. 15,16) On the other hand, clinical studies also revealed that glucocorticoids could red...

show abstract

Association Between IL-1 β /TNF- α –Induced Glucocorticoid-Sensitive Changes in Multiple Gene Expression and Altered Responsiveness in Airway Smooth Muscle

Cited by 77 publications

References 53 publications

Endothelin-1 Induces Expression of Matrix-associated Genes in Lung Fibroblasts through MEK/ERK

Endothelin-1 Induces Expression of Matrix-associated Genes in Lung Fibroblasts through MEK/ERK

Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients

Mechanism of Inhibitory Effect of Prednisolone on RhoA Upregulation in Human Bronchial Smooth Muscle Cells

Contact Info

Product

Resources

About