Opposing actions of (R,R)-isomers and (S,S)-isomers of formoterol on T-cell function.
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Adrenergic beta-Agonists↗
Biomedical subjects
John W Steinke
Publications and source records attributed to John W Steinke.
Proinflammatory effects of IL-4 antagonism.
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Cells, Cultured↗
Lysophosphatidic acid stimulates inflammatory cascade in airway epithelial cells.
Nasal polyps are benign outgrowths originating from the anterior ethmoid and maxillary sinuses. The events leading to polyp formation are unknown but evidence points to damage of the mucousal epithelium. Lysophosphatidic acid (LPA) is a water-soluble phospholipid that has been implicated in the development of allergic inflammation. We hypothesized LPA may be an important mediator in the initiation and maintenance of the inflammatory milieu of the polyp. Data was compared from unstimulated lung epithelial and when possible nasal polyp-derived epithelial cells with LPA stimulated cells. LPA receptors 1 and 2 were constitutively expressed on lung and nasal polyp-derived epithelial cells and receptor mRNA expression was decreased upon stimulation with IL-13 and IFN-gamma. When cells were treated with LPA, cellular proliferation was stimulated 2.2 fold. Supernatants from LPA stimulated cells displayed decreases in the levels of VEGF, GM-CSF, and TNF-alpha at 24h which returned to normal or increased at 48h. Our results suggest epithelial cells undergo rapid proliferation in response to LPA resulting in a transient decrease in inflammatory cytokines followed by an upregulation of these cytokines that could lead to increased inflammation.
Cell Proliferation↗
The relationship between rhinosinusitis and asthma sinusitis.
Chronic sinusitis comprises numerous disorders characterized by inflammation, mucous gland hyperplasia, and remodeling. Chronic hyperplastic eosinophilic sinusitis (CHES) is characterized by unrestrained proliferation of eosinophils, Th2-like lymphocytes, fibroblasts, goblet cells, and mast cells. The pathology of CHES is similar to that of asthma, and it is frequently diagnosed in association with asthma. It has been reported that exacerbations of CHES occur temporally with worsening of asthma; however, in the absence of well-controlled studies, this linkage remains unproven. In this article, the potential mechanisms linking these two diseases are examined.
Asthma↗
3. Cytokines and chemokines.
Cytokines and chemokines are secreted proteins with growth, differentiation, and activation functions that regulate the nature of immune responses. Cytokines are involved in nearly every facet of immunity and inflammation, from induction of the innate immune response to the generation of cytotoxic T cells and the development of antibodies by the humoral immune system. The combination of cytokines that are produced in response to an immune insult determines which arm of the immune system will be activated. For this update, recent advances in our understanding of cytokines will be discussed, which includes the IL-10, IL-17, and IL-27 families.
Animals↗
Genetics of allergic disease.
Currently, more than 20.3 million Americans report having asthma and an even greater number suffer from allergies. The cost for treatment of these dis-eases in the United States is greater than $8 billion with more than 40% of this total representing drug expenditure [59]. An intense effort has been made to understand the genetic components of asthma and allergies and how the identified genetic differences influence disease progression and response to drugs. In the future, it will be possible in the clinical setting to analyze a patient's genetic repertoire. From this information, the physician will gain in-sight into the genes involved in producing that subject's allergic and asthmatic phenotype; understand the natural history of that patient's disease;and predict responses (positive and negative) to pharmacologic agents. The end result will be the ability to tailor a specific treatment regime for each patient and reduce the overall cost of health care related to allergies and asthma.
Asthma↗
Fungi in chronic hyperplastic eosinophilic sinusitis: reasonable doubt.
Chronic hyperplastic eosinophilic sinusitis (CHES) is a T-helper (Th)2-like, lymphocyteinitiated, eosinophil-rich inflammatory disease. The complex immune interactions required to orchestrate these processes begin with the presentation of antigen by mature dendritic cells to Th lymphocytes that display the appropriate antigen-specific T-cell receptor. The objective of sinus research must be to identify and target that antigen; this will lead to the cure for this condition. This article reviews numerous models that may be responsible for the pathophysiology of this disorder, including putative roles for allergens, bacteria, and bacterial-derived superantigens, as well as recent interest in fungal-derived antigens. Additionally, we speculate that whatever the inciting cause of CHES may be, it is plausible that once initiated, cellular differentiation pathways may lead to the development of an antigen-independent permanent phase. More than one of these may be valid in different subjects and, furthermore, this list almost assuredly does not explain all cases of CHES. The concept that fungal antigens colonizing the sinuses are responsible for CHES represents an intriguing, but unproven, hypothesis. Presently, the case for the fungus remains circumstantial. The case for fungi will be proved only with definitive proof that T-cells within the sinuses are actively responding to fungal antigens present in the sinus and with the further demonstration that removal of those fungal antigens ameliorates the disease.
Antigens, Bacterial↗
Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease.
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a disease of intense eosinophilic inflammation that can produce fibrosis, hyperplasia, and remodeling. OBJECTIVE: To investigate the usefulness of quantifying severity of chronic hyperplastic eosinophilic sinusitis in predicting the presence of AERD. METHODS: Data were compared between asthmatic patients who reported exacerbations after aspirin ingestion and those who did not. The primary outcome measure was severity of sinusitis using a validated computed tomography (CT) scan-based scoring system. Indices of lower airway remodeling and other markers of inflammation were also evaluated. RESULTS: Twenty-one patients with AERD were compared with 19 patients with aspirin-tolerant asthma (ATA). Patients were well matched for asthma severity as shown by their similar lung function as measured by postbronchodilator forced expiratory volume in 1 second. Patients with AERD were distinguished by their sinus CT scores (AERD patients: 16.9; 95% confidence interval [CI], 13.4-21.3; ATA patients: 6.2; 95% CI, 4.2-9.1; P < .001), and they were considerably more likely to have nasal polyps (AERD patients: 90%; ATA patients: 26%; P < .001). In addition, AERD patients demonstrated increased total lung capacity (AERD patients: 107.9%; 95% CI, 99.9%-117.6%; ATA patients: 98.0%; 95% CI, 93.7%-102.5%; P = .05), reflecting a trend toward increased air trapping. No significant differences occurred in diffusing capacity, exhaled nitric oxide, eosinophilia, or exhaled breath condensate pH. CONCLUSIONS: AERD can be distinguished from ATA by the extent of hyperplasia on CT scan and the presence of nasal polyps. We hypothesize that AERD represents a remodeling process that affects both the upper and lower airways.
Adult↗
Functional analysis of -571 IL-10 promoter polymorphism reveals a repressor element controlled by sp1.
Transcriptional dysregulation of the IL-10 gene may contribute to the development and severity of autoimmune, infectious, neoplastic, and allergic diseases. A C to A base substitution has been identified at -571 bp in the IL-10 promoter and has been linked to immune diseases. The role of this polymorphism in IL-10 promoter function was assessed using luciferase reporter constructs. The presence of an A at -571 (A allele) increases promoter activity compared with that of a promoter with a C at this position (C allele). Binding of nuclear extract proteins from IL-10-producing human cell lines to DNA sequences including this base exchange and flanking sequences was demonstrated using EMSAs. Specific binding of the transcription factors Sp1 and Sp3 was demonstrated to a region immediately upstream of the polymorphism. No differences in the binding affinity of recombinant Sp1 were observed between the two forms of the promoter. Reconstitution of Sp1 expression decreased IL-10 promoter function in an Sp1-deficient cell line, demonstrating that this element functions as a repressor. The C to A base exchange relieves the repression mediated by Sp1. Individuals carrying the A allele of the IL-10 promoter may display increased synthesis of IL-10, resulting in suppressed immune responses and a modulation of their susceptibility to autoimmune, infectious, neoplastic, or atopic disease.
B-Lymphocytes↗
Leukotriene receptors in rhinitis and sinusitis.
Cysteinyl leukotrienes (CysLTs) mediate their biologic activities through interactions with the CysLT1 and CysLT2 receptors. CysLT1 receptors are prominently expressed on smooth muscle cells and lung fibroblasts, whereas CysLT2 receptors are expressed on heart Purkinje fiber cells, adrenal chromaffin cells, and endothelial cells. Both receptors are expressed on eosinophils and mast cells, but CysLT1 receptors alone are on neutrophils. Antigen-presenting cells more prominently express the type 2 receptor. CysLT1 receptors are uniquely important for bronchospasm, whereas CysLT2 receptors can stimulate endothelial cell adherence, myofibroblast proliferation, and chemokine production by mast cells. Comprehensive inhibition of the proinflammatory activities of CysLTs might require either combination CysLT1 and CysLT2 receptor antagonists or inhibitors of the CysLT synthesis pathway.
Chronic Disease↗
Anti-interleukin-4 therapy.
Interleukin 4 (IL-4) mediates important pro-inflammatory functions in asthma, including T helper cell type 2 lymphocyte differentiation, induction of IgE production, up-regulation of IgE receptors, expression of vascular cell-adhesion molecule 1, promotion of eosinophil transmigration into the lungs, inhibition of T-lymphocyte apoptosis, and mucus hypersecretion. The role of IL-4 in the pathogenesis of asthma is supported by identification of polymorphisms linked to asthma in the IL-4 gene promoter and proteins involved in IL-4 signaling. Several approaches to IL-4 antagonism are or have been in clinical development. This article examines IL-4 and the antagonists that have been developed. Early trial results and the future of anti-IL-4 therapy are discussed.
Antibodies, Monoclonal↗
Identification of an Sp factor-dependent promoter in GCET, a gene expressed at high levels in germinal center B cells.
Antigen-stimulated B lymphocytes undergo genetic and phenotypic changes in germinal centers (GCs), including affinity maturation of immunoglobulin (Ig) genes and Ig heavy chain isotype switching. Expression of the Germinal Center Expressed Transcript (GCET) gene is up-regulated in murine GC B cells. The human homolog of GCET, HGAL/GCET2, is an important prognostic marker for staging lymphomas derived from GCs. To identify mechanisms that control cell type-specific transcription of GCET, we localized promoter sequences using S1 nuclease protection and functional assays. Sequences comprising a TATA-less promoter were localized to a short region upstream of multiple mRNA start sites. In functional assays, the promoter is active in cells irrespectively of endogenous GCET gene expression. In vitro binding assays identified a non-consensus binding site for Sp factors near sites of transcriptional initiation. The site binds Spl and Sp3 in nuclear extracts and recombinant Spl in vitro, and is required for full promoter function in transient promoter assays. Activation of the promoter by Spl or Sp3 in Spl/3-deficient cells was largely dependent on the Sp site. Together, these data provide the first analysis of regulatory modules necessary for GCET expression, a model for GC B cell-specific transcription.
Animals↗
The role of allergy in chronic rhinosinusitis.
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Chronic Disease↗
Characterization of interleukin-4-stimulated nasal polyp fibroblasts.
Chronic hyperplastic eosinophilic sinusitis is an inflammatory disease that results in the accumulation of eosinophils, fibroblasts, mast cells, and goblet cells at the site of injury. A common feature of this disease is the presence of nasal polyposis (NP). The current studies were designed to assess the contribution of interleukin (IL)-4 to fibroblast-mediated inflammation in chronic hyperplastic eosinophilic sinusitis/NP. In addition, we hypothesized that cysteinyl leukotrienes (CysLT) may directly influence fibroblast-mediated fibrotic and remodeling pathways in this disorder. Fibroblasts were isolated from NP tissue. All fibroblast lines expressed the IL-4 receptor. IL-4 induced changes in mRNA and protein expression of fibrotic (transforming growth factor-beta1 and -beta2) and inflammatory cytokines and chemokines (IL-6 and CCL11) by fibroblasts as measured by semiquantitative and quantitative polymerase chain reaction, RNase protection assay, and enzyme-linked immunosorbent assay. The expression of CysLT and other proinflammatory lipid receptors on fibroblasts was evaluated. CysLT1 and CysLT2 receptors were not expressed on fibroblasts; however, LPA(1) receptor was constitutively expressed and LPA(2) receptor expression was upregulated by IL-4. The metabolic cascade involved in CysLT synthesis was not expressed in fibroblasts and could not be induced by IL-4 treatment.
Cell Line↗
2. Cytokines and chemokines.
Cytokines and chemokines are redundant secreted proteins with growth, differentiation, and activation functions that regulate and determine the nature of immune responses and control immune cell trafficking and the cellular arrangement of immune organs. Which cytokines are produced in response to an immune insult determines initially whether an immune response develops and subsequently whether that response is cytotoxic, humoral, cell-mediated, or allergic. A cascade of responses can be seen in response to cytokines, and often several cytokines are required to synergize to express optimal function. An additional confounding variable in dissecting cytokine function is that each cytokine may have a completely different function, depending on the cellular source, target, and, most important, specific phase of the immune response during which it is presented. Numerous cytokines have both proinflammatory and anti-inflammatory potential; which activity is observed depends on the immune cells present and their state of responsiveness to the cytokine. For this chapter, cytokines are grouped according to those that are mononuclear phagocytic-derived or T-lymphocytic-derived; that mediate cytotoxic (antiviral and anticancer), humoral, cell-mediated, or allergic immunity; and that are immunosuppressive. The biology of chemokines are then reviewed, grouped by family.
Animals↗
5. Genetics of hypersensitivity.
Genetics provides the basis for the host response to a variety of environmental factors that can play a role in the generation of complex genetic diseases, such as asthma and atopy. An understanding of the genetic bases for these conditions is therefore essential to understand their pathophysiology. Studies of the genetics of asthma and atopy have suffered from several daunting challenges. These include the recognition that these are conditions caused by numerous genes, with each gene assuming variable roles in different individuals. In addition, each gene presumably contributes only a small percentage to a given individual's genetic risk of asthma. This has led to the current situation, in which studies often demonstrate a lack of replication that can be explained by their being insufficiently powered. Furthermore, the pathophysiologies of asthma and atopy are incompletely understood, and the lack of clearly defined phenotypes also contributes to the inadequacies of the current literature. Nonetheless, regions of the human genome have been reproducibly associated with asthma and atopy. These regions have undergone intense study, and many genetic variants within them have been implicated as asthma and allergy genes. In addition, through candidate gene approaches, several genetic polymorphisms have been convincingly linked to increased risks for the development of asthma and atopy. Many of these genes are associated with alterations in responsiveness to therapeutic agents used in the treatment of these conditions. These genetic studies have an exciting potential for individually tailoring the therapeutic regimen to a given subject's genotype. It is to be hoped that they will also define new targets for the next generation of asthma and allergy therapeutic agents.
Animals↗
Cysteinyl leukotriene expression in chronic hyperplastic sinusitis-nasal polyposis: importance to eosinophilia and asthma.
BACKGROUND: Chronic hyperplastic eosinophilic sinusitis (CHS) results from the unregulated proliferation of eosinophils, T(H)2-like lymphocytes, goblet cells, mast cells, and fibroblasts and is present in most patients with asthma. The frequent coexpression of these disorders and their shared pathophysiology suggests that these are similar disorders affecting the upper and lower airways. OBJECTIVE: We evaluated the expression of cysteinyl leukotrienes (CysLTs) in sinus tissue from subjects with CHS compared with that seen in healthy sinus tissue. METHODS: Nasal polyp and sinus tissue was evaluated from 58 individuals undergoing elective functional endoscopic sinus surgery. The diagnosis of CHS was demonstrated through the presence of eosinophilia and activated (EG2(+)) eosinophils, as determined by means of tissue immunohistochemistry. Data were compared with those from both nasal polyp tissue without eosinophilic inflammation and healthy control sinus tissue obtained from the sinus ostiomeatal complex at the time of surgery for unrelated disorders. CysLTs were quantified by means of ELISA in lipid-extracted tissue. Activation of the metabolic pathway leading to CysLT synthesis was demonstrated by ribonuclease protection. Subjects were genotyped for leukotriene C(4) (LTC(4)) synthase C-to-A promoter polymorphism. RESULTS: CysLT concentrations were significantly higher in tissue obtained from subjects with CHS (776.7 +/- 201.9 pg/g tissue) compared with that seen in healthy sinus tissue (355.7 +/- 101.6 pg/g tissue, P <.03). CysLT concentrations within noneosinophilic nasal polyps (328.0 +/- 116.4 pg/g tissue) were similar to those in control tissue. The presence of CysLTs in CHS was associated with increased expression of LTC(4) synthase mRNA. The C-to-A promoter polymorphism was associated with trends toward the increased presence of CHS and CysLTs. CONCLUSIONS: CHS is characterized by the increased presence of CysLTs when compared with concentrations seen in tissue from patients with chronic inflammatory sinusitis or healthy sinus tissue. These studies support the use of LT modifiers as anti-inflammatory agents that might have clinical benefit in patients with these disorders.
Adult↗
Initiation site binding protein and the initiator-like promoter element of mouse mammary tumor virus.
The mouse mammary tumor virus (MMTV) promoter contains an element near its transcription initiation site that is recognized by a protein termed initiation site binding protein (ISBP). Spacing between the TATA box and the ISBP site is important for MMTV promoter function, as altered spacing results in heterogeneity in start site selection in vitro and in vivo. The sequence of the ISBP site is related to initiator elements common in many RNA polymerase II promoters. However, binding of partially purified ISBP to several promoters that contain well-characterized initiator elements was not detected; these promoters included binding sites for a number of previously identified initiator-binding proteins. Partially purified ISBP did, however, bind with high affinity to sequences near the initiation sites of the SV40 major late and adenovirus 2 E1B promoters.
Animals↗