Biomedical subjects

Ian M Adcock

Publications and source records attributed to Ian M Adcock.

At least 19 recordsLinked to original sources

PubMed2026

Genome-wide association study of asthma with high treatment burden and/or worse outcomes defined using electronic healthcare data in UK Biobank.

BACKGROUND: In ∼10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. METHODS: We used electronic healthcare records linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10-6) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. RESULTS: In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher body mass index compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma, but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence (BACH2, D2HGDH, IL1RL1, RPS26, SMAD3). CONCLUSION: We present the first use of electronic healthcare records in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

Journal Article↗

PubMed2006

IL-1 beta and TNF-alpha regulation of the adenosine receptor (A2A) expression: differential requirement for NF-kappa B binding to the proximal promoter.

Adenosine is a potent endogenous regulator of airway inflammation that acts through specific receptor subtypes that can either cause constriction (A1R, A2BR, and A3R) or relaxation (A2AR) of the airways. We therefore examined the effects of key inflammatory mediators on the expression of the A2AR in a lung epithelial cell line (A549). IL-1beta and TNF-alpha increased the expression of the A2AR gene at the mRNA and protein levels. In contrast, LPS had no effect on A2AR gene expression. IL-1beta and TNF-alpha rapidly activated p50 and p65, but not C-Rel, RelB, or p52, and both IL-1beta- and TNF-alpha-stimulated A2AR expression was inhibited by the IkappaB kinase 2 inhibitor AS602868 in a concentration-dependent manner. Using chromatin immunoprecipitation assays, we demonstrate that IL-1beta can enhance p65 association with putative kappaB binding sites in the A2AR promoter in a temporal manner. In contrast, TNF-alpha failed to enhance p65 binding to these putative sites. Functionally, the two most 5' kappaB sites were important for IL-1beta-, but not TNF-alpha-, induced A2AR promoter reporter gene activity. Finally, neither TNF-alpha nor Il-1beta had any effect on A2AR mRNA transcript degradation. These results directly implicate a major role for NF-kappaB in the regulation of A2AR gene transcription by IL-1beta and TNF-alpha but suggest that the effects of TNF-alpha on A2AR gene transcription are not mediated through the proximal promoter.

Cell Line, Tumor↗

PubMed2006

Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease.

The phosphoinositide 3-kinase(s) (PI3K) are a family of proteins that catalyze the phosphorylation of the 3-OH position of phosphoinositides and generate lipids that control a wide variety of intracellular signaling pathways. They are classified into three families according to their structure and substrate specificity and are thought to have distinct biological roles. Recent studies suggested that numerous components of the PI3K pathway play a crucial role in the expression and activation of inflammatory mediators, inflammatory cell recruitment, immune cell function, airway remodeling, and corticosteroid insensitivity in chronic inflammatory respiratory disease. Selective PI3K inhibitors have been developed that reduce inflammation and some characteristics of disease in experimental animal models. Targeting specific PI3K isoforms that may be overexpressed or overactive in disease should allow for selective treatment of respiratory diseases. Encouraging data from animal models, primary cells and clinical studies in other diseases suggest that inhibitors of PI3K/Akt may prove to be useful novel therapies in the treatment of asthma and chronic obstructive pulmonary disease.

Animals↗

PubMed2006

Expression of nonmuscle cofilin-1 and steroid responsiveness in severe asthma.

BACKGROUND: Glucocorticoids are the mainstay of asthma therapy; however, a proportion of patients with asthma has a severe form of the disease that fails to respond to therapy. Understanding the molecular mechanisms behind glucocorticoid-insensitive asthma is therefore of clinical importance. Evidence in glucocorticoid-unresponsive Henrietta Lack (HeLa) cells indicated that cofilin-1 could act as an inhibitor of glucocorticoid function. OBJECTIVE: To determine whether cofilin-1 expression is abnormally expressed in cells from patients with severe glucocorticoid-insensitive asthma and examine the effect of cofilin-1 overexpression on glucocorticoid function. METHODS: Peripheral blood CD4(+) T cells were purified from 16 subjects with severe glucocorticoid-insensitive asthma and 16 subjects with mild glucocorticoid-sensitive asthma, and cofilin-1 expression was determined by quantitative real-time RT-PCR and Western blotting. The effect of dexamethasone on cofilin-1 expression was determined in Jurkat T cells, and the effect of cofilin-1 overexpression on anti-CD3/CD28-stimulated IL-2 release was measured. RESULTS: Peripheral blood CD4(+) T cells from subjects with severe glucocorticoid-insensitive asthma are less responsive to dexamethasone than cells from subjects with mild glucocorticoid-sensitive asthma. Cells from these patients express significantly (P < .05) higher levels of cofilin-1 than cells from subjects with mild asthma. Dexamethasone did not affect cofilin-1 expression in Jurkat T cells. Functionally, dexamethasone suppression of anti-CD3/CD28-stimulated IL-2 was attenuated in Jurkat cells overexpressing cofilin-1. CONCLUSION: These results suggest that increased cofilin-1 expression may be important in the regulation of glucocorticoid sensitivity in peripheral blood lymphocytes of patients with severe treatment-insensitive asthma. CLINICAL IMPLICATIONS: Understanding the mechanisms of enhanced cofilin-1 expression may lead to the development of new therapies for severe treatment-insensitive asthma.

Adult↗

PubMed2006

Cytokine production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease.

BACKGROUND: T lymphocytes (predominantly CD8+ cells) have previously been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). OBJECTIVE: We sought to describe the profile of cytokine production by CD8+ and CD4+ cells isolated from bronchoalveolar lavage fluid. METHODS: Bronchoalveolar lavage was performed in 11 patients with COPD (median FEV1, 63.3% of predicted value) and 9 healthy control subjects. CD8+ and CD4+ T cells were isolated by means of positive selection after macrophage depletion. CD8+ and CD4+ cells were activated with anti-CD3/CD28 antibodies for 60 hours before restimulation with phorbol 12-myristate 13-acetate-ionomycin and brefeldin. Three-color flow cytometry was used to simultaneously measure levels of intracellular cytokines. RESULTS: IL-4 was expressed by a higher percentage of stimulated CD8+ T cells (TC2) compared with CD4+ T cells (TH2) in patients with COPD (P = .01). In contrast, IFN-gamma was expressed in a significantly higher percentage of stimulated CD4+ T cells (TH1) than CD8+ T cells (TC1) in the COPD group (P = .04). TNF-alpha was expressed by almost all TC1 and TH1 cells, with virtually no expression by TC2 and TH2 cells. In addition, a small number of T cells expressing TNF-alpha alone without concomitant IFN-gamma or IL-4 expression were seen in the majority of subjects. There was a higher percentage of TC2 cells in subjects with COPD compared with that seen in the control group (P = .03). Stimulation with anti-CD3/CD28 antibodies increased the percentage of TC2 cells and decreased the percentage of TH2 cells. CONCLUSION: Our results suggest that there are increased numbers of TC2-like cytokine-expressing cells in the lungs of patients with COPD. CLINICAL IMPLICATIONS: These cells might be a source of TH2 cytokines, which might, at least in part, explain the lung eosinophilia associated with COPD exacerbations.

Adult↗

PubMed2006

Kinase inhibitors and airway inflammation.

Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function and airway remodelling. Important kinases such as Inhibitor of kappaB kinase (IKK)2, mitogen activated protein (MAP) kinases and phsopho-inositol (PI)3 kinase regulate inflammation either through activation of pro-inflammatory transcription factors such as activating protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), which are activated in airway disease, or through regulation of mRNA half-life. Selective kinase inhibitors have been developed which reduce inflammation and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or over active in disease should allow for selective treatment of respiratory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukaemia viral oncogene (Abl) kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myelogenous leukaemia. Encouraging data from animal models and primary cells and early Phase I and II studies in other diseases suggest that inhibitors of p38 MAP kinase and IKK2 may prove to be useful novel therapies in the treatment of severe asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and other inflammatory airway diseases.

Animals↗

PubMed2006

Epigenetics and airways disease.

Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.

Arginine↗

PubMed2006

NF-kappaB and activator protein 1 response elements and the role of histone modifications in IL-1beta-induced TGF-beta1 gene transcription.

Abnormal expression of TGF-beta1 is believed to play an important role in the pathogenesis of a number of chronic inflammatory and immune lung diseases, including asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Gene activation in eukaryotes requires coordinated use of specific cell signals, chromatin modifications, and chromatin remodeling. We studied the roles of the ubiquitous inflammatory transcription factors, NF-kappaB and AP-1, in activation of the TGF-beta1 gene and histone acetylation at the TGF-beta1 promoter. IL-1beta-induced TGF-beta1 protein secretion and mRNA expression were prevented by actinomycin D and were attenuated by the inhibitor of kappaB kinase 2 inhibitor AS602868 and the JNK inhibitor SP600125, suggesting a degree of transcriptional regulation mediated by the NF-kappaB and AP-1 pathways. We demonstrated that IL-1beta activated the p65 subunit of NF-kappaB and the c-Jun subunit of AP-1. Using chromatin immunoprecipitation assays, we observed a sequential recruitment of p65 and c-Jun, accompanying ordered elevation of the levels of histone H4 and H3 acetylation and recruitment of RNA polymerase II at distinct regions in the native TGF-beta1 promoter. The specific NF-kappaB and AP-1 binding sites in the TGF-beta1 promoter were confirmed by an ELISA-based binding assay, and evidence for histone hyperacetylation in TGF-beta1 induction was supported by the observation that the histone deacetylase inhibitor trichostatin A enhanced basal and IL-1beta-induced TGF-beta1 mRNA expression. Our results suggest that IL-1beta-stimulated transcription of TGF-beta1 is temporally regulated by NF-kappaB and AP-1 and involves histone hyperacetylation at distinct promoter sites.

Acetylation↗

PubMed2006

Update on glucocorticoid action and resistance.

Extensive development of inhaled and oral glucocorticoids has resulted in highly potent molecules that have been optimized to target activity to the lung and minimize systemic exposure. These have proved highly effective for most asthmatic subjects, but despite these developments, there are a number of subjects with asthma who fail to respond to even high doses of inhaled or even oral glucocorticoids. Advances in delineating the fundamental mechanisms of glucocorticoid pharmacology, especially the concepts of transactivation and transrepression and cofactor recruitment, have resulted in better understanding of the molecular mechanisms whereby glucocorticoids suppress inflammation. The existence of multiple mechanisms underlying glucocorticoid insensitivity raises the possibility that this might indeed reflect different diseases with a common phenotype, and studies examining the efficacy of potential new agents should be targeted toward subgroups of patients with severe corticosteroid-resistant asthma who clearly require effective new drugs and other approaches to improved asthma control.

Anti-Asthmatic Agents↗

PubMed2006

Molecular mechanisms of respiratory virus-induced asthma and COPD exacerbations and pneumonia.

Lower airways inflammation is a central feature of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and pneumonia. Although the specific characteristics of the inflammatory responses and the site of inflammation differ between one disease to another, they always involve recruitment and activation of inflammatory cells and changes in structural cells of the lung. Inflammatory responses are associated with an increased expression of a cascade of proteins including cytokines, chemokines, growth factors, enzymes, adhesion molecules and receptors. In most cases the increased expression of these proteins is the result of enhanced gene transcription: many of these genes are not expressed in normal cells under resting conditions but they are induced in the inflammatory process in a cell-specific manner. Transcription factors regulate the expression of many pro-inflammatory genes and play a key role in the pathogenesis of airway inflammation. Many studies have suggested a role for viral infections not only as a causative agent of pneumonia but also of asthma and COPD exacerbations. In this review we will provide an overview of the relationship between common respiratory viral infections and the molecular mechanisms involved in the activation of airway inflammation and on the regulation of transcription factors in these inflammatory respiratory diseases. The relative importance of each transcription factor will be certainly greatly clarified in the next few years with the growing availability of specific inhibitors capable of blocking activation of a specific transcription factor. Clearly this is an exciting new area of ongoing research with promising therapeutic potential.

Anti-Inflammatory Agents↗

PubMed2006

New insights into the molecular mechanisms of corticosteroids actions.

Corticosteroids produce a marked improvement in clinical parameters in most asthmatic patients; in contrast, corticosteroids have little effect on lung function measurements in patients with chronic obstructive pulmonary disease. By uncovering the reason for this paradox, it should be possible to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic receptor, which is subjected to post-translational modifications. Receptor phosphorylation may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Other modifications such as nitration/nitrosylation may also affect glucocorticoid receptor function. Oxidative stress due to cigarette smoke may be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription and reduces glucocorticoid receptor-associated repressor functions. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.

Adrenal Cortex Hormones↗

PubMed2006

Histone deacetylase inhibitors as novel anti-inflammatory agents.

Histone acetylation regulates inflammatory gene expression and also plays a role in diverse functions such as DNA repair and cell proliferation. Changes in histone acetylation patterns have been reported in many human diseases, particularly cancer, and investigators have used histone deacetylase inhibitors (eg, suberoylanilide hydroxamic acid and MS-275) against many malignancies. In vitro and in vivo data in a number of cell types and animal models of disease indicate that selective histone deacetylase inhibitors may have the potential to act as anti-inflammatory agents possibly acting through non-histone proteins. More evidence is required concerning the long-term safety of these agents, for example, lung destruction, and in comparison with currently used therapies.

Animals↗

PubMed2005

Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression.

Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-kappaB-mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1beta-induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-kappaB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-kappaB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-kappaB-dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-kappaB-mediated, but not GRE-mediated, gene expression.

Cell Line, Tumor↗

PubMed2005

Cigarette smoke activates human monocytes by an oxidant-AP-1 signaling pathway: implications for steroid resistance.

Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smoking-induced pathophysiology is often resistant to the anti-inflammatory effects of glucocorticoids. The nature of cigarette smoke-induced inflammation is still not defined, although neutrophil recruitment and activation seem to be consistent features. In the current study, we have used a range of approaches to demonstrate that cigarette smoke activates human monocytes and macrophages to release the CXC chemokine CXCL8 [(interleukin-8 (IL-8)]. Furthermore, we show for the first time that cigarette smoke synergizes with proinflammatory cytokines IL-1beta and tumor necrosis factor-alpha, and it is this interaction that confers steroid resistance to smoke-induced CXCL8 release. We go on to show that smoke-induced activation of human cells is an oxidant-mediated phenomenon acting through activator protein-1, but not nuclear factor kappaB, pathway. These observations add significantly to our understanding of smoke as an inflammatory stimulus that has implications for potential the development of treatments of smoking or related disease.

Cells, Cultured↗

PubMed2005

Single-nucleotide polymorphisms associated with symptomatic infection and differential human gene expression in healthy seropositive persons each implicate the cytoskeleton, integrin signaling, and oncosuppression in the pathogenesis of human parvovirus B19 infection.

This study was undertaken to further examine the role of the host response to parvovirus B19 in the development of symptoms and consequences of viral persistence. Genomic DNA from 42 patients with symptomatic B19 infection was analyzed using the HuSNP assay (Affymetrix), and the results were compared with those from analysis of 53 healthy control individuals. Fifty-seven single-nucleotide polymorphisms were identified that were significantly associated with symptomatic infection. Total RNA from peripheral blood mononuclear cells from 57 B19-seropositive and 13 B19-seronegative donors was analyzed by hybridization to a single-color microarray representing 9522 human genes. Ninety-two genes were shown to be differentially expressed. Differential expression was confirmed in 6 of 38 genes (SKIP, MACF1, SPAG7, FLOT1, c6orf48, and RASSF5) tested using real-time quantitative polymerase chain reaction in a different group of healthy subjects. Genes identified in both studies play a functional role in the cytoskeleton, integrin signaling, and oncosuppression, themes that have been shown to be important in parvovirus infections.

Adolescent↗

PubMed2005

5-Azacytidine suppresses RNA polymerase II recruitment to the SLPI gene.

Histone methylation is regarded as a stable modification important in the epigenetic regulation of gene expression. Transcriptionally active chromatin is methylated at H3-K4 whereas repressed chromatin is methylated at H3-K9. To investigate the role of histone methylation in an acute inflammatory response, A549 cells were treated with IL-1beta and/or the methylase inhibitor 5-azacytidine (5-aza), and histone H3-K4 methylation levels and transcription of secretory leukocyte protease inhibitor (SLPI) were measured. IL-1beta stimulation enhanced histone H3-K4 tri-methylation across the SLPI coding region at 24h. In parallel, IL-1beta enhanced recruitment of RNA polymerase II to the SLPI gene. 5-aza attenuated both H3-K4 tri-methylation and RNA polymerase II recruitment to a similar extent resulting in reduced SLPI mRNA and protein levels. These data suggest that in addition to epigenetic regulation of constitutive SLPI expression, H3-K4 tri-methylation may play a role in stimulated SLPI expression by modulating RNA polymerase II recruitment and subsequent gene transcription.

Animals↗

PubMed2005

Decreased histone deacetylase activity in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages. METHODS: HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examined. Total RNA extracted from lung tissue and macrophages was used for quantitative reverse-transcriptase-polymerase-chain-reaction assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunoprecipitation assay. RESULTS: Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia. CONCLUSIONS: Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease.

Acetyltransferases↗

PubMed2005

Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy.

Clinical evidence is accumulating for the efficacy of adding inhaled long-acting beta(2)-agonists (LABAs) to corticosteroids in asthma. Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs), which then translocate to the nucleus where they regulate gene expression. This article reports the first evidence in vivo of an interaction between inhaled LABA and corticosteroid on GR nuclear translocation in human airway cells using immunocytochemistry. We initially demonstrated significant GR activation 60 minutes after inhalation of 800 microg beclomethasone dipropionate in six healthy subjects. Subsequently, we determined the effects of salmeterol and fluticasone propionate (FP) in seven steroid-naive patients with asthma. We observed dose-dependent GR activation with 100- and 500-microg doses of FP, and to a lesser extent with 50 microg salmeterol alone. However, combination therapy with 100 microg FP and salmeterol augmented the action of FP on GR nuclear localization. In vitro, salmeterol enhanced FP effects on GR nuclear translocation in epithelial and macrophage-like airway cell lines. In addition, salmeterol in combination with FP enhanced glucocorticoid response element (GRE)-luciferase reporter gene activity and mitogen-activated protein kinase phosphatase 1 (MKP-1) and secretory leuko-proteinase inhibitor (SLPI) gene induction. Together, our data confirm that GR nuclear translocation may underlie the complementary interactions between LABAs and corticosteroids, although the precise signal transduction mechanisms remain to be determined.

Adrenal Cortex Hormones↗