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Induction of airway mucus production By T helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production.

Cohn L, Homer RJ, Marinov A, Rankin J, Bottomly K - J. Exp. Med. (1997)

Bottom Line: When this defect in homing was overcome by administration of TNF-alpha, 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. lcohn@biomed.med.yale.edu

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-alpha, 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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Mucus production  and airway inflammation in mice  after transfer of cells and exposure to TNF-α and inhaled  OVA. BALB/c mice received  transfer of OVA-specific IL-4  +/+, IL-4 −/− Th2 cells or  naive CD4 T cells (N), then exposure to TNF-α and 7 d of inhaled OVA. (A) HMI was performed on lung sections stained  with DPAS. Mean HMI  (±SEM) is shown. (B) BAL cells  recovered from mice. Differential  counts were performed on  cytospins of cells recovered from  BAL of individual mice. Mean  cell counts (±SEM) are shown  (n = 4–5 mice per group). One  experiment is shown and is representative of three experiments.  Statistical significance was determined by unpaired Student's t  test. *P <0.02, IL-4 +/+ Th2  vs. IL-4 −/− Th2.
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Figure 7: Mucus production and airway inflammation in mice after transfer of cells and exposure to TNF-α and inhaled OVA. BALB/c mice received transfer of OVA-specific IL-4 +/+, IL-4 −/− Th2 cells or naive CD4 T cells (N), then exposure to TNF-α and 7 d of inhaled OVA. (A) HMI was performed on lung sections stained with DPAS. Mean HMI (±SEM) is shown. (B) BAL cells recovered from mice. Differential counts were performed on cytospins of cells recovered from BAL of individual mice. Mean cell counts (±SEM) are shown (n = 4–5 mice per group). One experiment is shown and is representative of three experiments. Statistical significance was determined by unpaired Student's t test. *P <0.02, IL-4 +/+ Th2 vs. IL-4 −/− Th2.

Mentions: To test if induction of adhesion molecules on the vascular endothelium would facilitate recruitment of OVA-specific IL-4 −/− Th2 cells to the lung, we transferred OVA-specific IL-4 +/+, IL-4 −/− Th2 cells or naive CD4 T cells into mice and treated the mice with inhaled TNF-α. TNF-α has previously been shown to increase both VCAM-1 and E-selectin expression on lung endothelium (45). Mice were then exposed to 7 d of inhaled OVA. As seen in Fig. 7 B, inflammation, as indicated by increased numbers of cells in the BAL, was observed in the mice that received IL-4 +/+ and IL-4 −/− Th2 cells, whereas mice that received naive CD4 T cells and TNF-α had minimal inflammation. Mucus staining was increased in the bronchial epithelium of mice that received IL-4 +/+ or IL-4 −/− Th2 cells and exposure to inhaled OVA (Fig. 7 A). Mice that received transfer of naive CD4 T cells, TNF-α and inhaled OVA did not show mucus staining in the bronchial epithelium.


Induction of airway mucus production By T helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production.

Cohn L, Homer RJ, Marinov A, Rankin J, Bottomly K - J. Exp. Med. (1997)

Mucus production  and airway inflammation in mice  after transfer of cells and exposure to TNF-α and inhaled  OVA. BALB/c mice received  transfer of OVA-specific IL-4  +/+, IL-4 −/− Th2 cells or  naive CD4 T cells (N), then exposure to TNF-α and 7 d of inhaled OVA. (A) HMI was performed on lung sections stained  with DPAS. Mean HMI  (±SEM) is shown. (B) BAL cells  recovered from mice. Differential  counts were performed on  cytospins of cells recovered from  BAL of individual mice. Mean  cell counts (±SEM) are shown  (n = 4–5 mice per group). One  experiment is shown and is representative of three experiments.  Statistical significance was determined by unpaired Student's t  test. *P <0.02, IL-4 +/+ Th2  vs. IL-4 −/− Th2.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199146&req=5

Figure 7: Mucus production and airway inflammation in mice after transfer of cells and exposure to TNF-α and inhaled OVA. BALB/c mice received transfer of OVA-specific IL-4 +/+, IL-4 −/− Th2 cells or naive CD4 T cells (N), then exposure to TNF-α and 7 d of inhaled OVA. (A) HMI was performed on lung sections stained with DPAS. Mean HMI (±SEM) is shown. (B) BAL cells recovered from mice. Differential counts were performed on cytospins of cells recovered from BAL of individual mice. Mean cell counts (±SEM) are shown (n = 4–5 mice per group). One experiment is shown and is representative of three experiments. Statistical significance was determined by unpaired Student's t test. *P <0.02, IL-4 +/+ Th2 vs. IL-4 −/− Th2.
Mentions: To test if induction of adhesion molecules on the vascular endothelium would facilitate recruitment of OVA-specific IL-4 −/− Th2 cells to the lung, we transferred OVA-specific IL-4 +/+, IL-4 −/− Th2 cells or naive CD4 T cells into mice and treated the mice with inhaled TNF-α. TNF-α has previously been shown to increase both VCAM-1 and E-selectin expression on lung endothelium (45). Mice were then exposed to 7 d of inhaled OVA. As seen in Fig. 7 B, inflammation, as indicated by increased numbers of cells in the BAL, was observed in the mice that received IL-4 +/+ and IL-4 −/− Th2 cells, whereas mice that received naive CD4 T cells and TNF-α had minimal inflammation. Mucus staining was increased in the bronchial epithelium of mice that received IL-4 +/+ or IL-4 −/− Th2 cells and exposure to inhaled OVA (Fig. 7 A). Mice that received transfer of naive CD4 T cells, TNF-α and inhaled OVA did not show mucus staining in the bronchial epithelium.

Bottom Line: When this defect in homing was overcome by administration of TNF-alpha, 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. lcohn@biomed.med.yale.edu

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-alpha, 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.

Show MeSH
Related in: MedlinePlus