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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TL;DR: The data suggested that triterpenoids fraction of Ganoderma tsugae might be the main constituents to alleviate allergic asthma.
Abstract: This study was to investigate antiallergic effects of triterpenoids (Gt-TRE) and polysaccharide (Gt-PS) extracts from Ganoderma tsugae, using mast cell line RBL-2H3, T cell line EL4, primary T cells, and transfected RAW264.7 macrophage cells. The results showed that histamine secreted from activated RBL-2H3 mast cells was significantly suppressed by Gt-TRE but not Gt-PS. Interleukin- (IL-) 4 secreted from activated EL4 cells was significantly suppressed by Gt-TRE but not Gt-PS. Further primary CD4
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Cites background from "Induction of Airway Mucus Productio..."
...Furthermore, IL-4 is crucial for eosinophils and lymphocytes recruitment to the lung and for induction of inflammation [44]....
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TL;DR: Differential expression of IFN‐γR and signaling through IFN-γ in the conjunctiva between the two strains is demonstrated, which may be due to differences in histopathological character between theTwo strains.
Abstract: Genetic background determines the histological features of experimental immune-mediated blepharoconjunctivitis (EC) in rats, which is a model for human allergic conjunctivitis (AC). A great number of lymphocytes predominate in EC of Lewis rats, while less lymphocytes and more eosinophils are present in that of Brown Norway (BN) rats. Although this difference could be attributed to their systemic Th1/Th2 dominancy, it remains unclear whether some regulatory mechanisms may exist in the inflammatory site in the conjunctiva. Here, we aim to investigate this hypothesis by comparing the expression levels of inflammatory mediators in the conjunctiva between the two strains. EC was induced in Lewis and BN rats by transfer of ovalbumin (OVA)-specific CD4+ T-cell lines followed by eye drops of OVA as antigen challenge, and then was clinically and histologically evaluated. Reverse-transcription (RT)-PCR was performed to compare the expressions of cytokines and cytokine receptors (Rs) in conjunctivas of both strains of rats either with or without EC. To confirm the biological significance of interferon (IFN)-γ R expression, phosphorylation of signal transducers and activators of transcription (STAT)-1 was examined in the conjunctivas, followed by subconjunctival injection of IFN-γ. BN T cells contained interleukin (IL)-4 and IFN-γ, while Lewis T cells expressed no IL-4. Transfer of those cells induced more severe EC in Lewis rats. RT-PCR using naive conjunctivas detected more IL-4, IFN-γ, and IFN-γR β-chain RNA expression in BN rats. After the EC induction, BN rats expressed significantly higher amounts of IFN-γR β-chain, and upregulation of interferon regulatory factor (IRF)-1 was observed. Phosphorylation of STAT-1 was more remarkable in BN rats. The findings demonstrate differential expression of IFN-γR and signaling through IFN-γ in the conjunctiva between the two strains. This may be due to differences in histopathological character between the two strains.
8 citations
01 Jan 2000
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Cites background or result from "Induction of Airway Mucus Productio..."
...Work in our and other laboratories has demonstrated the central role of CD4+ T cells and the cytokines they secrete (IL-4, IL-5 and IL-13) in the development of allergic inflammation and AHR (Gavett et al., 1994; Cohn et al., 1997; Keane-Myers et al., 1997; Hogan et al., 1998a; Hogan et al., 1998b; Keane-Myers et al., 1998b; Wills-Karp et al., 1998; Li et al., 1999a)....
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...The importance of CD4+ T cells and their products to allergic inflammation and AHR has been demonstrated in many models ( Gavett et al., 1994; Cohn et al., 1997; Keane-Myers et al., 1997; Hogan et al., 1998a; Hogan et al., 1998b; Keane-Myers et al., 1998; Wills-Karp et al., 1998; Li et al., 1999) and it appears that these provide help to CDS+ T cells in this model to induce pulmonary eosinophilia....
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...This demonstrated a fundamental role for CD4+ T cells in the regulation of baseline AHR and these results are consistent with many other studies, showing the central role of CD4+ T cells and the cytokines they secrete (IL-4, IL-5 and IL-13) in the development of allergic inflammation and AHR (Gavett et al., 1994; Cohn et al., 1997; Keane-Myers et al., 1997; Hogan et al., 1998a; Hogan et al., 1998b; Keane-Myers et al., 1998; Wills-Karp et al., 1998; Li et al., 1999)....
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TL;DR: Environmental and genetic factors together result in the development of a Th2-biased immune response and the overproduction of Th2 cytokines such as IL-4,IL-5, IL-9, and IL-13, which orchestrate the inflammation in allergy and asthma.
Abstract: Atopic diseases, which include asthma, allergic rhinitis, and atopic dermatitis, are complex genetic traits caused by environmental factors in genetically susceptible individuals. These disorders h...
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01 Jan 2017
TL;DR: In this article, we laten zien dat WNT groeifactoren op vele vlakken kunnen bijdragen aan de pathofysiologie van allergisch astma.
Abstract: Astma is een veelvoorkomende chronische ontstekingsziekte van de luchtwegen die wordt gekenmerkt door terugkerende symptomen, belemmering van de luchtstroom en bronchospasme. De luchtweg-gladde spier draagt in belangrijke mate bij aan deze toegenomen vernauwing, middels samentrekking, toename in massa, of aanmaak van ontstekingsfactoren. Waar het de gladdespier betreft richten de huidige therapien voor astma zich voornamelijk op luchtwegverwijding, maar voor de overige kenmerken, waaronder toegenomen massa, bestaat er nog geen specifieke behandelingsstrategie. In dit proefschrift gaan we in op de rol van zogenaamde WNT groeifactoren bij deze processen. We laten zien dat WNT groeifactoren op vele vlakken kunnen bijdragen aan de pathofysiologie van astma. Dit hebben we aangetoond met luchtweggladdespiercellen die we in kweek hebben gebracht, maar ook met transgene muizen die WNT groeifactoren overproduceren in de spier. Uit deze modellen hebben we geleerd dat de factor WNT-5A, die in de spier bij astma verhoogd aanwezig is, contractiliteit van de spier bevordert, en tevens wordt uitgescheiden door de cel, waar het ontstekingsbevorderende interactie kan aangaan met naburige ontstekingscellen. Ook blijken WNT groeifactoren betrokken bij spierverdikking. In allergeen-behandelde muizen kon spierverdikking worden voorkomen door deze signaaltransductieroute farmacologisch te remmen. Dit onderzoek toont aan dat WNT groeifactoren, in het bijzonder WNT-5A, bijdragen aan de chronische pathologie van allergisch astma. Farmacologische inhibitie van WNT groeifactoren kan zowel luchtwegverwijdend als ontstekingsremmend werken en tevens de spiermassa terugdringen. Zo creeert het onderzoek nieuwe inzichten in mogelijke toekomstige therapieen gericht op de chronische component van astma, waaronder spierverdikking, waarvoor tot op heden nog geen farmacologische behandeling bestaat.
8 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