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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 IL-4 +/+ or  IL-4 −/− Th2 cells and exposure  to inhaled OVA. BALB/c mice  received transfer of OVA-specific  IL-4 +/+ or IL-4 −/− Th2  cells and inhaled OVA. Controls  received no cells and inhaled  OVA. (A) HMI was performed  on lung sections stained with  DPAS. Mean HMI (±SEM) is  shown. (B) BAL cells recovered  from mice after exposure to 7 d  of inhaled OVA. Differential  counts were performed on  cytospins of cells recovered from  BAL of individual mice. Mean  cell counts (±SEM) are shown  (n = 4 mice per group). One  experiment is shown and is  representative of three experiments. Statistical significance was determined by unpaired Student's t test. *P <0.005, IL-4 +/+ Th2 vs. IL-4 −/− Th2. ‡P  <0.0001, IL-4 +/+ Th2 vs. IL-4 −/− Th2.
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Figure 6: Mucus production and airway inflammation in mice after transfer of IL-4 +/+ or IL-4 −/− Th2 cells and exposure to inhaled OVA. BALB/c mice received transfer of OVA-specific IL-4 +/+ or IL-4 −/− Th2 cells and inhaled OVA. Controls received no cells and inhaled OVA. (A) HMI was performed on lung sections stained with DPAS. Mean HMI (±SEM) is shown. (B) BAL cells recovered from mice after exposure to 7 d of inhaled OVA. Differential counts were performed on cytospins of cells recovered from BAL of individual mice. Mean cell counts (±SEM) are shown (n = 4 mice per group). One experiment is shown and is representative of three experiments. Statistical significance was determined by unpaired Student's t test. *P <0.005, IL-4 +/+ Th2 vs. IL-4 −/− Th2. ‡P <0.0001, IL-4 +/+ Th2 vs. IL-4 −/− Th2.

Mentions: Previous studies had shown that IL-4 overexpression in the airways resulted in mucus hypersecretion (7). To investigate the precise mechanism by which Th2 cells induced increased mucus staining, we began by studying the role of IL-4 in these processes. OVA-specific Th2 cells from IL-4–deficient (IL-4 −/−) mice or wild-type (IL-4 +/+) BALB/c mice were generated as has been described previously (41, 43). Mice were immunized with OVA in alum, and primed CD4 T cells were isolated and stimulated in vitro for 4 d with OVA in the presence of IL-4 and anti–IFN-γ. An aliquot of cells from each culture was restimulated in vitro in the presence of OVA and APCs, and supernatants were assayed for IFN-γ, IL-4, IL-5, and IL-10 (Table 2). IL-4 −/− OVA-specific Th2 cells produced comparable levels of IL-5 and IL-10 when compared to IL-4 +/+ OVA-specific Th2 cells, but IL-4 was produced only by IL-4 +/+ Th2 cells. CD4 Th2 cells were then transferred into BALB/c IL-4 +/+ recipients and the mice were exposed to inhaled OVA for 7 d. Control mice received no transferred cells and were exposed to inhaled OVA. In contrast to mice that received IL-4 +/+ Th2 cells, IL-4 −/− Th2 cells did not induce significant lung inflammation or mucus production (Fig. 6). Mice that received IL-4 −/− Th2 cells and inhaled OVA had a 10-fold reduction in total BAL cell recovery compared to mice that received IL-4 +/+ Th2 cells. Furthermore, eosinophils and lymphocytes were strikingly reduced in the BAL fluid. These data suggested that IL-4 −/− Th2 cells had either died or that production of IL-4 by the donor Th2 cell was necessary for its entry into the lung. Since staining of tissue sections revealed that VCAM-1 expression was markedly reduced in mice that received IL-4 −/− Th2 cells and inhaled OVA (data not shown; Cohn, L., manuscript in preparation) and since VCAM-1 expression on lung endothelium has previously been shown to be critical for both lymphocyte and eosinophil recruitment to the lung (44), these experiments suggested that the transferred IL-4 −/− Th2 cells were not recruited to the lung because of a defect in lymphocyte-endothelial adhesion.


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 IL-4 +/+ or  IL-4 −/− Th2 cells and exposure  to inhaled OVA. BALB/c mice  received transfer of OVA-specific  IL-4 +/+ or IL-4 −/− Th2  cells and inhaled OVA. Controls  received no cells and inhaled  OVA. (A) HMI was performed  on lung sections stained with  DPAS. Mean HMI (±SEM) is  shown. (B) BAL cells recovered  from mice after exposure to 7 d  of inhaled OVA. Differential  counts were performed on  cytospins of cells recovered from  BAL of individual mice. Mean  cell counts (±SEM) are shown  (n = 4 mice per group). One  experiment is shown and is  representative of three experiments. Statistical significance was determined by unpaired Student's t test. *P <0.005, IL-4 +/+ Th2 vs. IL-4 −/− Th2. ‡P  <0.0001, 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 6: Mucus production and airway inflammation in mice after transfer of IL-4 +/+ or IL-4 −/− Th2 cells and exposure to inhaled OVA. BALB/c mice received transfer of OVA-specific IL-4 +/+ or IL-4 −/− Th2 cells and inhaled OVA. Controls received no cells and inhaled OVA. (A) HMI was performed on lung sections stained with DPAS. Mean HMI (±SEM) is shown. (B) BAL cells recovered from mice after exposure to 7 d of inhaled OVA. Differential counts were performed on cytospins of cells recovered from BAL of individual mice. Mean cell counts (±SEM) are shown (n = 4 mice per group). One experiment is shown and is representative of three experiments. Statistical significance was determined by unpaired Student's t test. *P <0.005, IL-4 +/+ Th2 vs. IL-4 −/− Th2. ‡P <0.0001, IL-4 +/+ Th2 vs. IL-4 −/− Th2.
Mentions: Previous studies had shown that IL-4 overexpression in the airways resulted in mucus hypersecretion (7). To investigate the precise mechanism by which Th2 cells induced increased mucus staining, we began by studying the role of IL-4 in these processes. OVA-specific Th2 cells from IL-4–deficient (IL-4 −/−) mice or wild-type (IL-4 +/+) BALB/c mice were generated as has been described previously (41, 43). Mice were immunized with OVA in alum, and primed CD4 T cells were isolated and stimulated in vitro for 4 d with OVA in the presence of IL-4 and anti–IFN-γ. An aliquot of cells from each culture was restimulated in vitro in the presence of OVA and APCs, and supernatants were assayed for IFN-γ, IL-4, IL-5, and IL-10 (Table 2). IL-4 −/− OVA-specific Th2 cells produced comparable levels of IL-5 and IL-10 when compared to IL-4 +/+ OVA-specific Th2 cells, but IL-4 was produced only by IL-4 +/+ Th2 cells. CD4 Th2 cells were then transferred into BALB/c IL-4 +/+ recipients and the mice were exposed to inhaled OVA for 7 d. Control mice received no transferred cells and were exposed to inhaled OVA. In contrast to mice that received IL-4 +/+ Th2 cells, IL-4 −/− Th2 cells did not induce significant lung inflammation or mucus production (Fig. 6). Mice that received IL-4 −/− Th2 cells and inhaled OVA had a 10-fold reduction in total BAL cell recovery compared to mice that received IL-4 +/+ Th2 cells. Furthermore, eosinophils and lymphocytes were strikingly reduced in the BAL fluid. These data suggested that IL-4 −/− Th2 cells had either died or that production of IL-4 by the donor Th2 cell was necessary for its entry into the lung. Since staining of tissue sections revealed that VCAM-1 expression was markedly reduced in mice that received IL-4 −/− Th2 cells and inhaled OVA (data not shown; Cohn, L., manuscript in preparation) and since VCAM-1 expression on lung endothelium has previously been shown to be critical for both lymphocyte and eosinophil recruitment to the lung (44), these experiments suggested that the transferred IL-4 −/− Th2 cells were not recruited to the lung because of a defect in lymphocyte-endothelial adhesion.

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