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Journal ArticleDOI

Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production

Lauren Cohn1, Robert J. Homer1, Anthony Marinov1, John A. Rankin1, Kim Bottomly1 
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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Journal ArticleDOI
TL;DR: ST218 was an excellent anti-allergy strain that can be favorable to use in the treatment or prevention of allergic diseases, and had a better suppressive effect in vivo.

9 citations

Journal ArticleDOI
TL;DR: There were inconsistent changes in the serum PON1 activity of mice infected with T. spiralis, and these changes were associated with significant increases in the plasma levels of interleukin (IL-2), IL-4, IL-10, Il-12, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor α while the levels of IL-5 and interferon γ were significantly increased throughout the entire experimental period.
Abstract: Infections with gastrointestinal nematodes provoke immune and inflammatory responses mediated by cytokines released from T-helper type-2 (Th2) cells. Infections with Trichinella species have been reported to differ by the host species. Previously, in rats, we observed acute liver inflammation in response to infection with Trichinella spiralis, and the rat hosts showed a series of biochemical changes characterized by a decrease in serum paraoxonase (PON) 1 activity associated with the down-regulation of hepatic PON1 synthesis. In the present study, we investigated the effect(s) of species differences on the immune response against T. spiralis infection by analyzing serum PON1 activity and the associated inflammatory/anti-inflammatory mediators in mice. There were inconsistent changes in the serum PON1 activity of mice infected with T. spiralis, and these changes were associated with significant increases in the serum levels of interleukin (IL)-2, IL-4, IL-10, IL-12 (p70), granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor α during the enteric phase of the infection, while the levels of IL-5 and interferon γ were significantly increased throughout the entire experimental period. Moreover, T. spiralis infection in mice was associated with little inflammatory cell infiltration in hepatic tissues. Given the zoonotic prevalence of T. spiralis, further mechanistic research in this area is warranted.

9 citations


Cites background from "Induction of Airway Mucus Productio..."

  • ...[9] who proposed that TNF-α increases Th2 cell transendothelial migration, thereby potentiating mucosal Th2 responses during enteric helminth infection [14]....

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Journal ArticleDOI
TL;DR: HSP65-induced effects on allergen-induced airway hyperresponsiveness and inflammation were associated with increased Delta1 expression on dendritic cells, modulation of dendrite cell function, and CD4+ Th1 cytokine production.
Abstract: Heat shock proteins (HSPs), produced in response to stress, are suppressive in disease models. We previously showed that Mycobacterium leprae HSP65 prevented development of airway hyperresponsiveness and inflammation in mice. Our goal in this study was to define the mechanism responsible for the suppressive effects of HSP. In one in vivo approach, BALB/c mice were sensitized to OVA, followed by primary OVA challenges. Several weeks later, HSP65 was administered prior to a single, provocative secondary challenge. In a second in vivo approach, the secondary challenge was replaced by intratracheal instillation of allergen-pulsed bone marrow-derived dendritic cells (BMDCs). The in vitro effects of HSP65 on BMDCs were examined in coculture experiments with CD4(+) T cells. In vivo, HSP65 prevented the development of airway hyperresponsiveness and inflammation. Additionally, Th1 cytokine levels in bronchoalveolar lavage fluid were increased. In vitro, HSP65 induced Notch receptor ligand Delta1 expression on BMDCs, and HSP65-treated BMDCs skewed CD4(+) T cells to Th1 cytokine production. Thus, HSP65-induced effects on allergen-induced airway hyperresponsiveness and inflammation were associated with increased Delta1 expression on dendritic cells, modulation of dendritic cell function, and CD4(+) Th1 cytokine production.

9 citations


Cites background from "Induction of Airway Mucus Productio..."

  • ...lenge in mice, was sufficient to induce airway eosinophilia and AHR (54, 55)....

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01 Jan 2014
TL;DR: Maternal asthma during pregnancy is associated with alterations in peripheral blood DNA methylation in infants’ and Inflammatory phenotypes of asthma are associated with differential DNAmethylation in peripheralBlood monocytes, suggesting possible implications in the disease pathogenesis.
Abstract: Asthma is an inflammatory disease that manifests in the airways. There are an estimated 300 million people worldwide currently suffer from asthma. Common asthma symptoms include dyspnea and wheezing. These are consequences of the reversible airflow obstruction associated with airway inflammation. The symptoms can be mild or can be as severe as life threatening depending on nature of underlying inflammation. Although heredity plays a role in the disease pathogenesis, the high and rising prevalence of asthma, particularly in recent decades highlights a strong influence of the environment. To this end, epigenetic phenomena including alteration of DNA methylation and chromatin structure are likely contributors to the pathogenesis of asthma as well as a plausible source of phenotype heterogeneity. Especially subtle alteration of DNA methylation patterns which occur early in life may impact on disease development. However, the exact role of epigenetic mechanisms in the pathogenesis of asthma and inflammatory phenotypes of asthma are not well understood. This thesis investigates; 1) Alterations in infant peripheral blood DNA methylation profiles associated with pre-natal exposure to maternal asthma, 2) The role of chromatin structure by analysing histone acetyl-transferases (HAT) and histone de-acetylases (HDAC) activity of peripheral blood monocytes in inflammatory phenotypes of adult asthma, 3) Alterations in the DNA methylation profile of peripheral blood monocytes associated with inflammatory phenotype of adult asthma. The primary findings of this thesis are: 1) Maternal asthma during pregnancy is associated with alterations in peripheral blood DNA methylation in infants’. 2) Inflammatory phenotypes of asthma are associated with differential DNA methylation in peripheral blood monocytes. Gene network analyses of these differentially methylated genes revealed distinct molecular pathways, suggesting possible implications in the disease pathogenesis.

9 citations

01 Jan 2019
TL;DR: It is demonstrated that DGKζ plays immunomodulatory roles during Th2 differentiation and in the non-hematopoietic compartments to regulate type 2 immune-mediated disease and reveals that the inflammatory and AHR components of asthma are not as interdependent as generally believed.
Abstract: Type 2 helper T cells (Th2) are beneficial for orchestrating protective immune responses against helminths but can also be pathogenic in settings of allergy and asthma. Weak TCR-mediated extracellular signal-regulated kinase (ERK) signals are thought to promote Th2 differentiation in vitro. However, it was unclear whether selective enhancement of specific TCR-mediated signal transduction pathways could suppress Th2 differentiation in vitro and block Th2 inflammation in vivo in a polyclonal setting. The lipid molecule diacylglycerol (DAG) is the main driver of TCR-mediated ERK activation. Here, we demonstrate that T cells lacking DAG kinase-ζ (DGKζ), a negative regulator of DAG, display impaired Th2 differentiation in vitro. Accordingly, mice lacking DGKζ exhibited decreased type 2 airway inflammation and were almost completely resistant to airway hyperresponsiveness (AHR) in vivo in an OVA-induced mouse model of allergic asthma. Surprisingly, we found that the mechanisms by which DGKζ protected against airway inflammation and AHR were separable. Conditional deletion of DGKζ in T cells led to decreased type 2 airway inflammation with no attenuation of AHR. In contrast, conditional deletion of DGKζ in airway smooth muscle cells led to diminished AHR with no attenuation of airway inflammation. Mechanistically, T-cell specific enhancement of ERK signaling was sufficient to diminish Th2 differentiation in vitro and attenuate type 2 airway inflammation with no changes in AHR in vivo. These data demonstrate that specific enhancement of DAG signaling downstream of the TCR is sufficient to attenuate Th2 differentiation in an ERK-dependent manner. Furthermore, our findings reveal that the inflammatory and AHR components of asthma are not as interdependent as generally believed. Additionally, we also demonstrate a novel role for DGKζ in regulating protease allergen-mediated type 2 airway inflammation. We found that global but not hematopoietic-specific ablation of DGKζ was sufficient to protect from papain-induced airway inflammation. Further analysis revealed that protection from papain in the absence of DGKζ might be potentially due to an impairment in IL-33 production/release in response to papain. Collectively, this thesis highlights that DGKζ plays immunomodulatory roles during Th2 differentiation and in the non-hematopoietic compartments to regulate type 2 immune-mediated disease. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Immunology First Advisor Taku Kambayashi

8 citations


Cites background from "Induction of Airway Mucus Productio..."

  • ...29 the type 2 cytokines, IL-4, IL-5, and IL-13, in response to antigen-dependent and antigen-independent activation (159-166)....

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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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Journal ArticleDOI
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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Journal ArticleDOI
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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Journal ArticleDOI
21 Dec 1990-Science
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

Journal ArticleDOI
01 Nov 1991-Science
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