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Abstract |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Remodeling of the airways, as occurs in asthmatic patients, is
associated with the continual presence of inflammatory mediators and Th2 cytokines, especially interleukin (IL)-13, during
cycles of epithelial injury and repair. In this study, we examined the effect of IL-13 on well-differentiated normal human
bronchial epithelial (NHBE) cells maintained in air-liquid interface culture. IL-13 induced proliferation of NHBE cells after
24 h exposure, as reflected by [3H]thymidine uptake and cell
counts. The effects of IL-13 were mediated through the epidermal growth factor receptor (EGFR), as proliferation was attenuated by AG1478, an EGFR tyrosine kinase inhibitor. Proliferation appeared to be mediated by transforming growth
factor (TGF)-
, a potent ligand for EGFR, which was released rapidly from NHBE cells in response to IL-13. Neutralizing antibody to TGF-, but not antibodies against other potentially
important growth factors (EGF, heparin binding epidermal
growth factor-like growth factor [HB-EGF], platelet-derived
growth factor [PDGF]), inhibited the mitogenic response to
IL-13. This study provides the first experimental evidence that
IL-13 can initiate a proliferative response of human airway epithelium in the absence of inflammatory cells or other cell
types. The results are consistent with a mechanism whereby
IL-13 induces release of TGF- from the epithelial cells, which
in turn binds via an autocrine/paracrine-type action to the
EGFR, initiating proliferation. IL-13-induced airway remodeling in vivo may involve this epithelium-driven response.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Airway remodeling, a major lesion in patients with asthma and other chronic inflammatory airway diseases, may involve perpetuation of the epithelial injury/repair cycle by the chronic presence of inflammatory mediators. Th2 cytokines, especially interleukin (IL)-13, have been implicated in the generation of a number of responses related to asthma and airway remodeling (1). IL-13 levels are greatly increased in lavage fluid from allergen-challenged patients with asthma (6). In addition, IL-13 is associated with airway hyperresponsiveness (1), inflammation, eosinophilia, goblet cell hyperplasia, mucus hyperproduction (1, 4, 5) and subepithelial fibrosis (2) in murine models of asthma.
Although the precise pathogenesis remains unknown, epithelial cells have been found to undergo proliferation in remodeling airways (7). The epidermal growth factor receptor (EGFR) has been shown to be important in remodeling that occurs in response to toxin-induced airway injury (11). The EGFR also has been implicated in development of mucous cell hyperplasia in animal models (3, 12).
As a potent ligand for the EGFR (13, 14), transforming
growth factor (TGF)- may be of major importance in the
remodeling process. TGF- is produced by numerous types
of epithelia in response to different insults (15, 16), and
the autocrine/paracrine function of TGF- and the EGFR
is a common theme in regulation of proliferating tissues,
including intestinal cancers, papillary thyroid carcinomas,
olfactory and mammary epithelium (17), and developing fetal tissue (21, 22).
In this study, we hypothesized that proliferation of airway epithelium could be initiated by direct interaction between IL-13 and epithelial cells, and that this response
could be mediated by TGF- produced by the epithelial
cells themselves. TGF- produced in response to IL-13
stimulation could then act, via an autocrine/paracrine-type mechanism, to bind to the EGFR and induce proliferation.
The results show that IL-13 can induce proliferation of differentiated normal human bronchial epithelial (NHBE)
cells in vitro via a mechanism involving the EGFR. This
IL-13-induced proliferative response was inhibited by a
neutralizing anti-TGF- antibody, but not by antibodies to
other growth factors. Additionally, IL-13 provoked release of soluble TGF- from these cells. Because the epithelial cell cultures are devoid of other cell types (e.g., leukocytes), the results suggest the presence of a TGF-/
EGFR autocrine/paracrine loop in NHBE cells that can be
activated by IL-13. This mechanism may relate to proliferation and remodeling in the airways of patients with asthma.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Reagents
NHBE cells and bronchial epithelial growth media (BEGM) and
supplements were purchased from Clonetics Corporation (Walkersville, MD). Transwell membranes were from Costar Corporation (Cambridge, MA). TGF- enzyme-linked immunosorbent
assay (ELISA) kits and AG1478 were purchased from Calbiochem (La Jolla, CA). Anti-EGF and anti-HB-EGF antibodies
were purchased from Santa Cruz Biotechnology (Santa Cruz,
CA), while TGF-, anti-TGF-, and anti-PDGF antibodies, and
goat total IgG, were from R&D Diagnostics (Minneapolis, MN). All other reagents, except those used for cell culture listed below,
were from Sigma (St. Louis, MO).
NHBE Cell Culture
NHBE cells from three different donors were expanded and grown
as described previously (23). Briefly, after expansion, NHBE cells
(passage 2) were plated at a density of ~ 35,000 cells/cm2 on 12-well transwell membranes coated for 1 h with 50 µg/ml rat-tail collagen, type I (Collaborative Research, Bedford, MA). Initially, the cells were kept submerged in a 50:50 mix (vol:vol) of
BEGM:Dulbecco's modified Eagle's medium with high glucose
(DMEM-H) and supplements including 0.13 mg/ml bovine pituitary extract, 5 × 10
8 M all-trans retinoic acid, 1 µg/ml bovine serum albumin (Intergen, Purchase, NY), 0.5 ng/ml EGF, 0.5 µg/ml
hydrocortisone, 5 µg/ml insulin, 10 µg/ml transferrin, 0.5 µg/ml
epinephrine, and 6.5 ng/ml triiodothyronine (Clonetics). Medium
was changed every other day until the cells reached confluence
between Days 6 and 8 in culture, at which time the apical medium
was removed while the basolateral medium was changed daily.
For the purposes of this study, Day 0 was defined as the day the
cells reached confluence in culture. In addition, the air-liquid interface was established on this day (Day 0). Experimentation was
performed on Day 9 after confluence when mature secretory
cells are prominent.
[3H]Thymidine Incorporation Assay
NHBE cells were grown to confluence in air-liquid interface. Cells were grown without EGF for 24 h before the [3H]thymidine incorporation assay. Cultures then were incubated with 1 µCi/ml [3H]thymidine (specific activity = 87.1 Ci/mmol) together with specific reagents described below. After incubation for the indicated time period, the medium was removed and the cultures washed 3× with ice-cold phosphate-buffered saline. The entire Transwell inserts were then removed and placed in 1 ml of scintillation fluid, and incorporated radioactivity analyzed in a LKB 1209 RACKBETA liquid scintillation counter. In addition, cells were counted using a hemocytometer.
Exposures of NHBE Cells
NHBE cells were exposed on Day 9. All experiments were done using cells from at least two different donors, and utilized concentrations of growth factors and inhibitors that exhibited no cytotoxicity to NHBE cells as determined by lactate dehydrogenase (LDH) assay. Determination of cytotoxicity by LDH assay was performed as previously described for air-liquid interface cultures (24).
Proliferation in response to IL-13. IL-13 (10 ng/ml) was added both basolaterally and apically to Day 9 cells for 24 h, after which time [3H]thymidine incorporation and cell counts were assessed.
Role of EGFR in IL-13- and TGF-
induced proliferation.
Cells were exposed for 24 h to IL-13 (10 ng/ml) in the presence or absence of the specific EGFR tyrosine kinase inhibitor AG1478 (0.1, 1, 5 µg/ml) (25, 26), after which thymidine incorporation was
measured as described above.
Role of TGF- in IL-13-induced proliferation. To determine
whether or not TGF- was involved in the proliferative response to IL-13, effects of neutralizing antibodies to TGF- and a number of other potentially important growth factors (e.g., epidermal growth factor [EGF]; platelet-derived growth factor [PDGF]; and heparin-binding epidermal growth factor-like growth factor [HB-EGF]) on IL-13-induced proliferation were assessed. Initial studies utilized a range of concentrations (50, 5, 0.5 µg/ml; data not shown) to determine an optimal concentration of anti-TGF-
antibody that affected proliferation in response to IL-13. Thus,
this optimal concentration (0.5 µg/ml) was used for all subsequent neutralizing antibody studies. Day 9 (well-differentiated)
cells were exposed to 0.5 µg/ml of the above neutralizing antibodies together with IL-13 (10 ng/ml) and [3H]thymidine, as described above, for 24 h, at which time proliferation was measured
as described above.
Release of TGF- by NHBE Cells in Response to IL-13
Day 9 cells were exposed to IL-13 (10 ng/ml) in the presence of
complete culture medium apically and basolaterally for either 1 or 3 h, at which time apical media were analyzed for the presence of soluble TGF- using a commercially available ELISA (Calbiochem, LaJolla, CA) according to the manufacturer's guidelines.
Data Analysis
The SigmaStat 2.03 software package from SPSS, Inc. (Chicago,
IL) was used for all analyses. For analysis of [3H]thymidine uptake data, one-way analysis of variance (ANOVA) with appropriate post-test correction for multiple comparisons was performed. Soluble TGF- ELISA data were analyzed using a Student's t test. Data were considered significant at P < 0.05. Replicates (2 to 8) of entire experiments were performed, and representative data are presented as means ± standard error of the mean (SEM).
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Proliferative Response to IL-13
To determine whether IL-13 can induce proliferation of NHBE cells, [3H]thymidine incorporation in primary cultures exposed to IL-13 was examined. [3H]thymidine incorporation was increased significantly following a 24-h exposure to IL-13 in Day 9 cells (P < 0.001, n = 12) (Figure 1). This finding correlated with a significant increase in total cell number in Day 9 cells exposed to IL-13 (10 ng/ml) for 24 h as assessed by counting. These data demonstrate that NHBE cells proliferate in response to IL-13.
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IL-13 Induces Proliferation via EGFR
To determine whether or not the EGFR is involved in IL-13-
induced proliferation, NHBE cells were incubated for 24 h
with IL-13 (10 ng/ml) together with the compound AG1478,
a specific inhibitor of EGFR tyrosine kinase activity (25).
AG1478 blocked [3H]thymidine incorporation in these
cultures in a concentration-dependent manner (Figure
2A). When AG1478 was added together with TGF- (5 ng/
ml), a concentration-dependent inhibition of [3H]thymidine
incorporation was observed similar to the effects of AG1478
on IL-13-induced proliferation (Figure 2B). These data indicate that both IL-13- and TGF--induced proliferation
of NHBE cells is mediated by the EGFR.
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Significantly different from
primary treatment (P < 0.01).
TGF- Mediates IL-13-Induced Proliferation
Because IL-13 is not known to serve directly as a ligand
for the EGFR, we examined the ability of a variety of neutralizing antibodies against known growth factors to block
IL-13-induced proliferation of NHBE cells. Anti-TGF-
antibody at a concentration of 0.5 µg/ml completely
blocked IL-13-induced proliferation (P < 0.005, n = 6);
other neutralizing antibodies (anti-EGF, anti-HB-EGF, anti-PDGF, and total IgG) at the same concentration had
no significant effect (Figure 3). As an additional control,
anti-TGF- antibody at 5 µg/ml also blocked [3H]thymidine incorporation in these cells in response to exogenously applied TGF- (5 ng/ml), indicating specificity of
the neutralizing antibody for TGF- (Figure 3). Thus, IL-13-induced proliferation of NHBE cells appears to be mediated by TGF-.
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significantly different from TGF-TGF- is a member of the EGF family of ligands, and
increased levels of TGF- have been documented in several hyperproliferative epithelial disorders (27). Following short incubations of NHBE cells with IL-13, ELISA
was used to examine media for soluble TGF- released by
the cells. Within 1 h, and maintained through 3 h of exposure, a significant (P < 0.05, n = 3) increase in soluble TGF- compared with control cultures was observed (Figure 4). Thus, IL-13 induces a rapid increase in release of
soluble TGF- from NHBE cells, and this growth factor
appears to mediate subsequent proliferation of these cells.
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Discussion |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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IL-13 has been shown to play a key role in the pathogenesis of asthma and remodeling of inflamed airways (1).
This report provides the first evidence that IL-13 can directly initiate a proliferative response in human airway epithelium. The mechanism responsible for this proliferation
appears dependent on IL-13-induced release of epithelial-derived TGF-, a growth factor that can bind to the EGFR
and initiate proliferation. Importantly, the results indicate
that proliferation of epithelial cells in response to IL-13
can occur in the absence of other cell types, such as neutrophils or eosinophils, and that the epithelium itself is a
source of TGF-.
Whereas this response occurred in vitro, one would anticipate similar effects of IL-13 in vivo, where its increased
levels in airways of allergen-challenged patients with asthma
have been documented (6). Upon allergen challenge, the
level of IL-13 in lavage fluid from patients with asthma has
been shown to be in the range of 0.4-3 ng/ml (6). Hence,
the concentration of IL-13 (10 ng/ml) used in these studies
is comparable to the concentration of IL-13 available to
interact with airway epithelium in vivo in diseased airways.
As illustrated in Figure 4, IL-13 induces release of 100-300
pg/ml of TGF- from NHBE cells in vitro after 1 h of exposure. We have observed that 500 pg/ml TGF- can
cause direct proliferation of these cells, further confirming
the ability of TGF- to act as the sole ligand mediating IL-13-induced NHBE cell proliferation. This potential mechanism is further confirmed, as the mitogenic effect of even a
10-fold higher concentration of TGF- (5 ng/ml) was attenuated by neutralizing antibodies against this growth factor.
IL-13-induced proliferation also was inhibited by concentrations of the EGFR tyrosine kinase inhibitor AG1478 (1, 5 µg/ml) similar to those found to be effective in attenuating activity of this kinase in primary pulmonary myofibroblasts exposed to TGF- (26). Taken together, these observations suggest that the cytokines, growth factors, and
other reagents involved in these studies of IL-13-induced
proliferation of NHBE cells in vitro appear to do so at
(patho)physiologic concentrations relevant to the in vivo situation.
Based on the results of these studies, the most likely
scenario for IL-13-induced proliferation of NHBE cells is
that IL-13 induces release of soluble TGF-, that in turn
binds to the EGFR on these cells and initiates proliferation. The EGFR exists as a heterodimer, and the various
heterodimeric receptor chains have different affinities for
ligands composing the EGF growth factor family. The
EGFR chain with the highest affinity for TGF- is the
EGFR (or HER1) polypeptide chain (13, 14). The EGFR
is capable of forming homodimers or heterodimers with
HER3 or HER4 chains. Upon binding TGF-, initiation
of tyrosine phosphorylation of these chains is dependent
on cell type (14). The inhibitory effects of AG1478 and
neutralizing TGF- antibodies on IL-13-induced proliferation observed in this study suggest TGF- is involved integrally in this proliferative response.
Inflammatory mediators may be present for prolonged
periods of time in diseased airways, and it is believed that
this chronic inflammation contributes to the profound airway remodeling observed in patients with long-term respiratory illnesses. In preliminary studies from our laboratory, we have reported that long-term exposure of NHBE
cells to IL-13 also provokes release of soluble TGF- (30).
In addition, long-term IL-13 exposure increases the percentage of Alcian blue/PAS-positive, mucus-producing cells
in these cultures (31), suggesting a possible link between
the long-term presence of IL-13 and development of a mucous phenotype in airway epithelium. Although both IL-13
and the EGFR have been implicated in development of
mucous cell hyperplasia during airway remodeling (3), it remains to be seen whether the TGF-/EGFR proliferative response described in this study plays a direct role in
development of this lesion.
Whereas the experiments reported here were performed in vitro, the model epithelial system used develops well-differentiated epithelial cells, similar in structure and function to human airway epithelium in vivo. Recognizing the limitations of this in vitro system, the results of this study highlight the potential contribution of the airway epithelium itself to possible mechanisms of airway remodeling. Whereas precise mechanisms regulating all aspects of airway remodeling remain to be elucidated, it appears that interactions between IL-13 and the human airway epithelium have the potential to provoke a number of responses related to remodeling, and to do so in the absence of additional inflammatory cells.
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Footnotes |
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Address correspondence to: Linda D. Martin, Ph.D., Department of Anatomy, Physiological Sciences and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606. E-mail: linda_martin{at}ncsu.edu
(Received in original form June 25, 2001 and in revised form August 16, 2001).
Abbreviations: epidermal growth factor, EGF; epidermal growth factor receptor, EGFR; enzyme-linked immunosorbent assay, ELISA; interleukin, IL; heparin binding epidermal growth factor-like growth factor, HB-EGF; normal human bronchial epithelial, NHBE; platelet-derived growth factor, PDGF; transforming growth factor alpha, TGF-.
Acknowledgments: The authors gratefully acknowledge the technical assistance of Ms. Anne L. Crews. This work was supported by National Institutes of Health grants HL66236 (L.M.) and HL36982 (K.A.), and by the state of North Carolina.
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Introduction
Materials and Methods
Results
Discussion
References
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 E. Puchelle, J.-M. Zahm, J.-M. Tournier, and C. Coraux Airway Epithelial Repair, Regeneration, and Remodeling after Injury in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2006; 3(8): 726 - 733. [Abstract] [Full Text] [PDF]
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R. J. Homer, Z. Zhu, L. Cohn, C. G. Lee, W. I. White, S. Chen, and J. A. Elias Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L502 - L511. [Abstract] [Full Text] [PDF]
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S. M. Casalino-Matsuda, M. E. Monzon, and R. M. Forteza Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 581 - 591. [Abstract] [Full Text] [PDF]
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 N. Berkova, S. Lair-Fulleringer, F. Femenia, D. Huet, M.-C. Wagner, K. Gorna, F. Tournier, O. Ibrahim-Granet, J. Guillot, R. Chermette, et al. Aspergillus fumigatus conidia inhibit tumour necrosis factor- or staurosporine-induced apoptosis in epithelial cells Int. Immunol., January 1, 2006; 18(1): 139 - 150. [Abstract] [Full Text] [PDF]
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 J. A. Voynow, B. M. Fischer, B. C. Roberts, and A. D. Proia Basal-like Cells Constitute the Proliferating Cell Population in Cystic Fibrosis Airways Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 1013 - 1018. [Abstract] [Full Text] [PDF]
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 J. R. McDermott, N. E. Humphreys, S. P. Forman, D. D. Donaldson, and R. K. Grencis Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection J. Immunol., September 1, 2005; 175(5): 3207 - 3213. [Abstract] [Full Text] [PDF]
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 P-R Burgel and J A Nadel Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium Thorax, November 1, 2004; 59(11): 992 - 996. [Abstract] [Full Text] [PDF]
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 H. W. Chu, S. Balzar, G. J. Seedorf, J. Y. Westcott, J. B. Trudeau, P. Silkoff, and S. E. Wenzel Transforming Growth Factor-{beta}2 Induces Bronchial Epithelial Mucin Expression in Asthma Am. J. Pathol., October 1, 2004; 165(4): 1097 - 1106. [Abstract] [Full Text] [PDF]
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T. D. Le Cras, W. D. Hardie, G. H. Deutsch, K. H. Albertine, M. Ikegami, J. A. Whitsett, and T. R. Korfhagen Transient induction of TGF-{alpha} disrupts lung morphogenesis, causing pulmonary disease in adulthood Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L718 - L729. [Abstract] [Full Text] [PDF]
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S.-Z. Wang, Y.-X. Bao, C. L. Rosenberger, Y. Tesfaigzi, J. M. Stark, and K. S. Harrod IL-12p40 and IL-18 Modulate Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection J. Immunol., September 15, 2004; 173(6): 4040 - 4049. [Abstract] [Full Text] [PDF]
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J. A. Whitsett, C. J. Bachurski, K. C. Barnes, P. A. Bunn Jr., L. M. Case, D. N. Cook, D. Crooks, M. W. Duncan, L. Dwyer-Nield, R. C. Elston, et al. Functional Genomics of Lung Disease Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2/S1): S1 - S81. [Full Text] [PDF]
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T. Kikuchi, J. D. Shively, J. S. Foley, J. M. Drazen, and D. J. Tschumperlin Differentiation-dependent responsiveness of bronchial epithelial cells to IL-4/13 stimulation Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L119 - L126. [Abstract] [Full Text] [PDF]
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W. Wu, J. M. Samet, R. Silbajoris, L. A. Dailey, D. Sheppard, P. A. Bromberg, and L. M. Graves Heparin-Binding Epidermal Growth Factor Cleavage Mediates Zinc-Induced Epidermal Growth Factor Receptor Phosphorylation Am. J. Respir. Cell Mol. Biol., April 1, 2004; 30(4): 540 - 547. [Abstract] [Full Text] [PDF]
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W. D. Hardie, T. D. Le Cras, K. Jiang, J. W. Tichelaar, M. Azhar, and T. R. Korfhagen Conditional expression of transforming growth factor-{alpha} in adult mouse lung causes pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L741 - L749. [Abstract] [Full Text] [PDF]
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H. C. Atherton, G. Jones, and H. Danahay IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L730 - L739. [Abstract] [Full Text] [PDF]
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J. A. Elias, C. G. Lee, T. Zheng, Y. Shim, and Z. Zhu Interleukin-13 and Leukotrienes: An Intersection of Pathogenetic Schema Am. J. Respir. Cell Mol. Biol., April 1, 2003; 28(4): 401 - 404. [Full Text] [PDF]
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B. M. Fischer, J. G. Cuellar, M. L. Diehl, A. M. deFreytas, J. Zhang, K. L. Carraway, and J. A. Voynow Neutrophil elastase increases MUC4 expression in normal human bronchial epithelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2003; 284(4): L671 - L679. [Abstract] [Full Text] [PDF]
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 J. L. Ingram, A. Rice, K. Geisenhoffer, D. K. Madtes, and J. C. Bonner Interleukin-13 Stimulates the Proliferation of Lung Myofibroblasts via a Signal Transducer and Activator of Transcription-6-Dependent Mechanism: A Possible Mechanism for the Development of Airway Fibrosis in Asthma Chest, March 1, 2003; 123(2007): 422S - 424S. [Full Text] [PDF]
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B. B. Vargaftig and M. Singer Leukotrienes, IL-13, and chemokines cooperate to induce BHR and mucus in allergic mouse lungs Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L260 - L269. [Abstract] [Full Text] [PDF]
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J. V. Fahy Goblet Cell and Mucin Gene Abnormalities in Asthma Chest, December 1, 2002; 122(6_suppl): 320S - 326S. [Abstract] [Full Text] [PDF]
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J. C. Bonner The epidermal growth factor receptor at the crossroads of airway remodeling Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L528 - L530. [Full Text] [PDF]
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