Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production
17 Nov 1997-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 186, Iss: 10, pp 1737-1747
TL;DR: It is suggested that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
Abstract: Airway inflammation is believed to stimulate mucus production in asthmatic patients. Increased mucus secretion is an important clinical symptom and contributes to airway obstruction in asthma. Activated CD4 Th1 and Th2 cells have both been identified in airway biopsies of asthmatics but their role in mucus production is not clear. Using CD4 T cells from mice transgenic for the OVA-specific TCR, we studied the role of Th1 and Th2 cells in airway inflammation and mucus production. Airway inflammation induced by Th2 cells was comprised of eosinophils and lymphocytes; features found in asthmatic patients. Additionally, there was a marked increase in mucus production in mice that received Th2 cells and inhaled OVA, but not in mice that received Th1 cells. However, OVA-specific Th2 cells from IL-4–deficient mice were not recruited to the lung and did not induce mucus production. When this defect in homing was overcome by administration of TNF-α, IL-4 −/− Th2 cells induced mucus as effectively as IL-4 +/+ Th2 cells. These studies establish a role for Th2 cells in mucus production and dissect the effector functions of IL-4 in these processes. These data suggest that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
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Dissertation•
23 Jul 2013
TL;DR: Novel data is presented indicating a role for epithelially expressed TSLPR to play in those responses to asthma, and what is known about both the immunological and epithelial responses that contribute to the pathogenesis of asthma is reviewed.
Abstract: The Regulation and Function of Thymic Stromal Lymphopoietin Receptor (TSLPR) in the Airway Epithelium Michael Miles Miazgowicz Chair of the Supervisory Committee: Affiliate Professor Steven F. Ziegler Department of Immunology The epithelially-derived cytokine thymic stromal lymphopoietin (TSLP) plays a key role in the development and progression of allergic disease and has notably been shown to directly promote the inflammatory responses that characterize asthma. Current models suggest that TSLP is produced by epithelial cells in response to inflammatory stimuli and acts upon hematopoietic cells to effect a TH2-type inflammatory response. Recent reports, however, have shown that epithelial cells themselves are capable of expressing the TSLP receptor (TSLPR), and may thus directly contribute to a TSLPdependent response. In this thesis, we review what is known about both the immunological and epithelial responses that contribute to the pathogenesis of asthma, and further present novel data indicating a role for epithelially expressed TSLPR to play in those responses.
4 citations
Journal Article•
TL;DR: IL-33 acts on lymphocytes of peripheral blood increasing secretion of Th2 cytokines and inhibiting inhibition of Th1 cytokines in asthmatic mice.
Abstract: BACKGROUND Allergic asthma is a chronic airway inflammatory disease partly characterised by high concentration of T help 2 (Th2) cytokines in bronchoalveolar lavage fluid (BALF). There is no report on the relation of peripherally circulating blood lymphocytes and asthma. We explored the balance of Th2/Th1 cytokines in asthmatic mice. Exogenous recombinant interleukin (IL) 33 acted on murine peripheral circulating blood lymphocytes, IL-5 cytokine was selected for assessing Th2 cytokines and interferon-gamma (IFN-γ) for Th1 cytokines. METHODS Female specific pathogen free BABL/c mice were sensitised by intraperitoneal injection of 20 µg of ovalbumin emulsified in 1 mg of aluminium hydroxide gel in a total volume of 200 µl, and challenged for 30 minutes in 7 consecutive days with an aerosol of 2 g ovalbumin in 100 ml of PBS. Then we collected BALF and isolated lymphocytes from the peripheral blood. The lymphocytes were divided into two groups: asthmatic group and normal group. Th1/Th2 cytokines was detected by enzyme-linked immunosorbent assay (ELISA) kits. RESULTS In the asthma group, we found numerous eosinophils and lymphocytes on the glass slides. We then confirmed that the optimal concentration of IL-33 was 10 ng/ml and time of IL-33 stimulating lymphocytes was 24 hours. In the asthma group, the production of IL-5 was significantly increased over normal group after stimulation with IL-33 (P < 0.05) and the production of IFNγ was supressed from IL-33 stimulated lymphocytes (P < 0.05). CONCLUSION IL-33 acts on lymphocytes of peripheral blood increasing secretion of Th2 cytokines and inhibiting secretion of Th1 cytokines.
4 citations
Cites background from "Induction of Airway Mucus Productio..."
...Simultaneously, IL-4 attracts Th2 cells into lung tissues and induce inflammation.(29) IL-13 is necessary and sufficient to induce airway hyperresponsiveness and eosinophil airway infiltration–it does not depend on IL-4 or IL-5....
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Dissertation•
14 Jun 2006
TL;DR: L'asthme est une maladie inflammatoire chronique des voies aeriennes dont l'incidence a augmente dramatiquement au cours of ces deux dernieres decennies, nous avons mis en evidence l'influence de cellules Natural Killer T invariantes (iNKT) dans le developpement de l' asthme allergique experimental.
Abstract: L'asthme est une maladie inflammatoire chronique des voies aeriennes dont l'incidence a augmente dramatiquement au cours de ces deux dernieres decennies. Chez les individus sensibles, cette inflammation induit des episodes de sifflements recurrents, une oppression thoracique, une secretion de mucus ainsi qu'une obstruction des voies respiratoires, un recrutement eosinophilique et une hyperreactivite broncho-pulmonaire (HRB). Les avancees dans la comprehension de la physiopathologie de l'asthme ont ete realisees grâce aux modeles experimentaux murins. Ces travaux ont mis en evidence le role de differentes cellules dans l'immunoregulation de l'inflammation bronchique, notamment les lymphocytes T de type Th2. Toutefois, les mecanismes immunologiques impliques dans la protection ou l'exacerbation de la maladie sont encore peu connus. Au cours de notre etude, nous avons mis en evidence l'influence de cellules Natural Killer T invariantes (iNKT) dans le developpement de l'asthme allergique experimental. Les cellules iNKT representent une population immunoregulatrice de lymphocytes T, caracterisee par l'expression d'une chaine alpha invariante du TCR (Va14Ja18 et Va24Ja18, respectivement chez la souris et chez l'homme) qui est positivement selectionnee par la molecule CD1d. Ces cellules synthetisent rapidement et massivement de nombreuses cytokines, comme l'IL-4 et l'IFN-g, lorsqu'elles sont simulees par l'a-galactosylceramide (a-GalCer), glycolipide reconnu specifiquement par les lymphocytes iNKT. Le spectre d'action attribue aux cellules iNKT est particulierement large. Elles sont impliquees dans le controle des reponses immunes contre des infections, des maladies autoimmunes, des modeles de contact de sensibilite et des tumeurs. En utilisant un modele ou les souris sont immunisees de facon systemique par l'ovalbumine (OVA) et ensuite stimulees au niveau des voies aeriennes par ce meme antigene (etape designee comme « challenge »), nous avons demontre que les cellules iNKT sont impliquees dans la severite de l'asthme allergique experimental. En effet, divers symptomes de l'asthme sont diminues chez les souris deficientes en cellules iNKT (Ja18-/-), notamment, l'inflammation eosinophilique, la production de cytokines de type Th2, comme l'IL-4 et l'IL-5, la secretion d'IgE et l'HRB. L'implication des cellules iNKT dans la severite de l'asthme a ete confirmee puisque le transfert adoptif des cellules iNKT a des souris Ja18-/- retablit les symptomes decrits ci-dessus. En nous basant sur ces resultats, nous nous sommes demandes si nous pourrions modifier la severite de l'asthme allergique en agissant sur les lymphocytes iNKT. Pour cela, nous avons traite des souris par l'a-GalCer. Nous avons ainsi demontre qu'une seule injection d'a-GalCer 1 h avant le premier challenge intranasal a des souris precedemment immunisees inhibait la totalite des symptomes de l'asthme. L'administration intranasal de l'a-GalCer inhibe les symptomes de l'asthme chez les souris immunisees et provoquees par l'OVA. Cette protection peut etre transferee chez des souris immunisees grâce a des cellules en provenance de souris traitees par l'a-GalCer. L'implication de l'IFN-g dans cette protection a ete mise en evidence par des anticorps neutralisants, ainsi que par le transfert de cellules iNKT en provenance de souris IFN-g-/-. En conclusion, nos resultats demontrent que les cellules iNKT sont impliquees dans la severite de l'asthme allergique experimental en activant la secretion de cytokines de type Th2 et que le traitement par l'a-GalCer, qui agit specifiquement sur les lymphocytes iNKT, inhibe le developpement de la maladie en induisant la secretion d'IFN-g. Ainsi, nos resultats suggerent que l'a-GalCer pourrait constituer un nouvel outil therapeutique dans le traitement de l'asthme allergique.
4 citations
Dissertation•
01 Jan 2001
TL;DR: Studies on the m olecular basis o fosinophil adhesion to endothelium and the role of EMTs in this process are reported on.
Abstract: Studies on the m olecular basis o f eosinophil adhesion to endothelium
4 citations
References
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Journal Article•
TL;DR: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished.
Abstract: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.
7,567 citations
"Induction of Airway Mucus Productio..." refers background in this paper
...The lower limit of sensitivity for each of the ELISAs was 0.6 ng/ml (IFNg ), 5 pg/ml (IL-4), 0.010 ng/ml (IL-5), and 200 pg/ml (IL-10)....
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...CD4 Th2 cells make a different panel of cytokines, including IL-4, IL-5, and IL-10 (17, 18)....
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...Assays were standardized with recombinant IFNg , IL-5, IL-10 (Endogen), and IL-4 (Collaborative Research, Inc.)....
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...1 A ), and IL-10 (data not shown)....
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...IL-4 2/2 OVA-specific Th2 cells produced comparable levels of IL-5 and IL-10 when compared to IL-4 1/1 OVA-specific Th2 cells, but IL-4 was produced only by IL-4 1/1 Th2 cells....
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TL;DR: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
Abstract: Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or...
2,898 citations
"Induction of Airway Mucus Productio..." refers background in this paper
...Th2 cells secreting IL-4 and IL-5 have been shown to be present and activated in the bronchial wall of asthmatic individuals (9, 23)....
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TL;DR: This paper used hybridoma monoclonal antibodies obtained after immunization of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes.
Abstract: Xenogeneic immunizations have the advantage of detecting a wide range of antigenic determinants because many commonly occurring proteins have diverged significantly during the course of evolution and are thus antigenic in other species. The broadness of xenogeneic responses, however, means that the antisera they produce are usually complex and require extensive absorptions to make them specific for a single antigen. This problem has now been overcome by generating hybridomas producing monoclonal antibodies (Kohler & Milstein 1975). These permit dissection ofthe xenogeneic response so that large amounts of individual antibodies can be obtained, each of which recognizes only one of the determinants recognized by a broadly reactive conventional antiserum. Williams et al. (1977) used hybridoma monoclonal antibodies obtained after immunizations of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes, i.e., differentiation antigens. Springer et al. (1978a) and Stern et al. (1978) used a similar approach to study mouse lymphocyte antigens. They prepared monoclonal antibodies by immunizing rats with mouse lymphocytes and showed that these monoclonals recognized previously undetected mouse cell surface determinants including a glycoprotein antigen that appears to be specific for macrophages (Springer et al. 1978b). Trowbridge (1978) also used rat anti-mouse immunizations to generate a monoclonal antibody against the non-polymorphic lymphocyte surface antigen T200.
1,916 citations
"Induction of Airway Mucus Productio..." refers methods in this paper
...To generate Th1 or Th2 cells from DO11.10 mice, CD4 T cells were isolated by negative selection as previously described (31) using mAbs to CD8 (clone 53-6.72, clone 2.43 [ 32 ]), Class II MHC I-A d (212.A1 [33]) and anti‐Ig-coated magnetic beads (Advanced Magnetics, Inc....
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TL;DR: Results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance in mice transgenic for a T cell receptor that reacts to this peptide.
Abstract: In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic for a T cell receptor (TCR) that reacts to this peptide contain thymocytes that progress from the immature to the mature phenotype. Intraperitoneal administration of the peptide antigen to transgenic mice results in a rapid deletion of the immature CD4+ CD8+ TCRlo thymocytes. Apoptosis of cortical thymocytes can be seen within 20 hours of treatment. These results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance.
1,831 citations
TL;DR: Some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo, but the serum levels of IgG1 and IgE are strongly reduced.
Abstract: Interleukin-4 (IL-4) promotes the growth and differentiation of many hematopoietic cells in vitro; in particular, it directs the immunoglobulin (Ig) class switch to IgG1 and IgE. Mice homozygous for a mutation that inactivates the IL-4 gene were generated to test the requirement for IL-4 in vivo. In the mutant mice T and B cell development was normal, but the serum levels of IgG1 and IgE were strongly reduced. The IgG1 dominance in a T cell-dependent immune response was lost, and IgE was not detectable upon nematode infection. Thus, some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo.
1,262 citations