American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 536-541, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.4682
Interleukin-13 Induces Goblet Cell Differentiation in Primary Cell Culture from Guinea Pig Tracheal Epithelium
Mitsuko Kondo,
Jun Tamaoki,
Kiyoshi Takeyama,
Junko Nakata and
Atsushi Nagai
First Department of Medicine, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan
Address correspondence to: Atsushi Nagai, M.D., First Department of Medicine, Tokyo Women's Medical University, School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: anagai{at}chi.twmu.ac.jp
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Abstract
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The Th2 cytokines, interleukin (IL)-4 and IL-13, bind to IL-4R , and cause goblet cell metaplasia/hyperplasia with increased mucin expression in vivo. However, there is not enough evidence that these cytokines directly induce mucin production in vitro. In this study, primary epithelial cells from guinea pig trachea were cultured at an air–liquid interface, and immediately after achieving confluence at Day 7 they were treated with human recombinant IL-4 or IL-13 for 14 d. IL-13–treated cells consisted of a large number of fully mature goblet cells with a smaller number of ciliated cells. Secretory granules of the goblet cells were positive for both periodic acid-Schiff and toluidine blue, and showed exocytosis. By contrast, IL-4 failed to induce goblet cell differentiation. The electric resistances of IL-13–treated cells were lower than those of IL-4–treated cells and nontreated cells, suggesting leaky epithelia. MUC5AC protein level in cell lysates measured by ELISA was several-fold higher in IL-13–treated cells than in nontreated cells, whereas the level in IL-4–treated cells was not changed. These data suggest that human recombinant IL-13, but not IL-4, can induce differentiation into mature goblet cells that produce MUC5AC protein in guinea pig tracheal epithelial cells in vitro.
Abbreviations: epidermal growth factor, EGF • enzyme-linked immunosorbent assay, ELISA • interleukin, IL • ovalbumin, OVA • peridoc acid-Schiff, PAS • phosphate-buffered saline, PBS • transmission electron microscopy, TEM
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Introduction
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It is widely accepted that Th2 lymphocytes play an important role in the pathophysiology of asthma (1). Th2 lymphocytes release various cytokines, such as interleukin (IL)-4, IL-5, and IL-13, which are key cytokines in allergic diseases. IL-5 causes eosinophilic inflammation, and IL-4 and IL-13 induce B cell IgE class switch and mucus hypersecretion. Furthermore, the airway epithelia of IL-4 and IL-13 transgenic mice show goblet cell metaplasia, and intratracheal instillations of IL-4 and IL-13 induce MUC5AC gene expression and goblet cell metaplasia in vivo (2–4). IL-4 operates through the IL-4 receptor (IL-4R) that is a heterodimer of IL-4R and either  c or IL-13R1, and IL-13 operates through IL-13R that is a heterodimer of IL-4R and IL-13R1 (5). Because IL-4R–deficient mice fail to show increased mucus production by airway epithelia in allergic models (6), IL-4R is critically important in goblet cell metaplasia. Although positive immunoreactivity for IL-4R has been shown in airway epithelial cells (7), it is unlikely that goblet cell metaplasia is induced by a direct action of IL-4 in vitro. For example, previous studies have shown that IL-4 inhibited mucus secretion and attenuated the gene expression of MUC5AC and MUC5B in primary human bronchial epithelial cells (8), and that IL-4 did not induce MUC5AC gene expression in mucoepidermoid carcinoma cell line, NCI-H292 (9). Concerning IL-13, Longphre and coworkers (10) reported that IL-13 did not increase MUC5AC gene expression in NCI-H292 cells, but it is uncertain whether IL-13 induces mucin production and MUC5AC expression in primary culture of lower airway epithelium.
We studied the effects of IL-4 and IL-13 on airway epithelial differentiation using air–liquid interface culture, a procedure that induces high levels of differentiation (11–13), with airway epithelial cells differentiating into both ciliated and goblet cells. In this study, we focused on the numbers of goblet cells and ciliated cells, because goblet cell hyperplasia along with correspondingly fewer ciliated cells may cause the impairment of mucociliary clearance that is found in the airways of patients who die of asthma (14). We also studied the effects of IL-4 and IL-13 on epithelial electric resistance using an Ussing chamber system, because the increase in airway epithelial permeability is another feature of asthma (15).
Like humans, guinea pigs have goblet cells in their tracheal mucosa. Therefore, guinea pigs are commonly used for mucus secretion experiments as animal models of asthma (16). Unfortunately, the gene sequences of guinea pig IL-4 and IL-13 are not known and these cytokines are not available at present. Therefore, we studied the effect of human recombinant IL-4/IL-13 on guinea pig tracheal epithelial differentiation.
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Materials and Methods
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As described previously (17), epithelial cells from guinea pig trachea were isolated by digestion with 0.075% protease (type XIV; Sigma Chemical Co., St. Louis, MO) at 4°C overnight. Cells were pelleted (200 g, 10 min) and suspended in a 50:50 mixture of Dulbecco's modified Eagle medium and Ham's F12 medium (GIBCO, Grand Island, NY) containing 5% fetal calf serum. Viability was  90% as assessed by trypan blue exclusion. Cells were plated at 2.5 x 105 cells per cm2 onto polycarbonate inserts of 12- or 24-mm diameter, 0.4-µm pore size, and 10-µm thickness (Costar Transwell, Cambridge, MA) which had been coated with vitrogen (Sigma). From the first day after plating, cells were cultured with serum-free, hormonally defined medium containing insulin (10 µg/ml; Sigma), transferrin (5 µg/ml; Sigma), triiodothyronine (20 ng/ml; Sigma), epidermal growth factor (EGF) (25 ng/ml; Sigma), all-trans retinoic acid (5 x 10-8 M; Sigma) and endothelial cell growth supplement (7.5 µg/ml; Sigma). After achieving confluence (Day 7), the apical medium was removed, and cells were fed from only the basolateral side with 1 or 2 ml of medium containing human recombinant IL-4 (10 ng/ml; Biosource International, Camarillo, CA) or human recombinant IL-13 (10 ng/ml; Biosource International). EGF was removed from the medium after confluence to avoid multilayer formation. Cells were maintained in an incubator under 20% O2 and 5% CO2 at 37°C, and culture media were changed once every 2 d.
Light and electron microscopic techniques have been described in detail elsewhere (18). In brief, the cells on porous filters were fixed with glutaraldehyde/osmium tetroxide, and embedded in epon. Thick sections were stained with toluidine blue for light microscopy. Thin sections (with a silver interference color) were stained with lead citrate and uranyl acetate for transmission electron microscopy (TEM).
For cell analysis, the total cell numbers were determined by counting epithelial cell nuclei over 1 mm of polycarbonate filter that corresponds to basement membrane in cross-sections of cultures with an oil immersion objective lens (x1,000) (19). The sections were randomly selected. The epithelial cells were classified as follows: ciliated cells contained ciliated borders and lightly stained cytoplasm; goblet cells contained abundant secretory granules in apical portion of the cytoplasm; and basal cells were small, flattened cells located just above the filter but not reaching the apical portion. The rest of the cells were defined as "others."
For assessment of mucin-specific staining by light microscopy, the cultured epithelial cells were rubbed off, transferred to glasses slides with a cytospin, and stained with periodic acid-Schiff (PAS)/alcian blue. Cross-sections of the cell sheet were also stained with PAS.
MUC5AC protein was measured by using enzyme-linked immunosorbent assay (ELISA) as described by Takeyama and coworkers (19). Cell lysates were prepared with phosphate-buffered saline (PBS) at multiple dilutions, and 50 µl of each sample was incubated with bicarbonate-carbonate buffer (50 µl) at 40°C in 96-well plate (Nunc, Roskilde, Denmark) until dry. Plates were washed three times with PBS and then incubated with 50 µl of mouse monoclonal MUC5AC antibody (clone 45 M1, 1:100; New Markers, Fremont, CA), which was diluted with PBS containing 0.05% Tween 20 (Sigma). After 1 h, the wells were washed three times with PBS, and 100 µl of horseradish peroxidase–goat anti-mouse IgG conjugate (1:10,000; Sigma) was added. After 1 h, plates were washed three times with PBS, color was developed with 3,3',5,5'-tetramethylbenzidine (TMB) peroxidase solution (Kirkegaard and Perry Laboratories, Gaithersburg, MD) and stopped with 1 M H2SO4. Absorbance was read at 450 nm. MUC5AC protein level was normalized by dividing by concentration of the total protein.
For assessment of electric properties, the cell sheets were mounted on conventional Ussing chamber and bathed with Krebs-Henseleit solution (pH 7.4), which was bubbled with 95% O2–5%CO2 at 37°C. Under open circuit condition, potential difference (PD) was measured. PD was clamped to zero, and the resulting short circuit current (Isc) was continuously displayed on a chart recorder. Resistance (R) was determined from the height of 0.2-s current pulses passed across short-circuit tissues at 20-s intervals so as to displace PD by 0.5 mV from zero.
Statistics
All data are expressed as mean ± SE. One-way ANOVA was used to determine statistically significant differences between groups. Scheffe's F test was used to correct for multiple comparisons when statistical significances were identified in the ANOVA. A P < 0.05 for the null hypothesis was accepted as indicating a statistically significant difference.
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Results
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Morphology
Figure 1 shows a TEM micrograph of native tracheal epithelium from guinea pigs. The goblet cells had many secretory granules with dense cores. TEM micrographs of cultured tracheal epithelial cells on Day 7 and Day 21 are shown in Figure 2. Cultured tracheal epithelial cells on Day 7, the date of conversion from immersion to air–liquid interface, consisted of undifferentiated cells with neither ciliated nor goblet cells (Figure 2A). On Day 21, nontreated cells (control cells) and IL-4–treated cells consisted of ciliated and undifferentiated cells, but goblet cells were rarely found (Figures 2B and 2C). By contrast, cells treated with IL-13 (10 ng/ml) consisted of a large number of fully differentiated goblet cells with smaller numbers of ciliated cells (Figure 2D). The secretory granules of the goblet cells were positive for both toluidine blue and PAS/alcian blue in light micrographs (Figures 3A–3C), and had internal compositions with various densities in TEM micrographs (Figure 3D). Some of these internal compositions resembled the dense cores surrounded by flocculent material in goblet cells of native epithelium (Figure 1). Some of the secretory granules were undergoing exocytosis (Figure 3D). The cell numbers of different cell type under the various growth conditions are shown in Table 1. Compared with control, IL-13 significantly reduced numbers of ciliated cells and increased the numbers of goblet cells. IL-4 had no significant effects.
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Figure 1. Photograph of transmission electron microscopy in native tracheal epithelium from guinea pigs. The goblet cells had many secretory granules with dense core. Scale bar, 10 µm.
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Figure 3. Characteristics of secretory granules in goblet cells induced by IL-13. (A) Photograph of light microscopy (toluidine blue stain). Most of the IL-13–treated cells at apical portion consist of goblet cells, whose granules are positively stained with toluidine blue. Original magnification: x1,000. (B) Photograph of light microscopy (PAS/alcian blue stain). Cytospins were prepared from cultured cell sheets dispersed by mechanical agitation. Secretory granules positioned at apical portion are positive for PAS/alcian blue stain (arrows). Original magnification: x1,000. (C) Photograph of light microscopy (PAS stain). Cross-section of the cell sheet shows PAS-positive secretory granules in the goblet cells. Original magnification: x400. (D) High-powered magnification photograph of secretory granules. Several granules are ready for exocytosis. One granule just finished exocytosis (arrow). Scale bar, 1 µm.
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MUC5AC Protein Levels
MUC5AC protein levels measured by ELISA are shown in Figure 4. IL-4 did not significantly alter MUC5AC protein levels. On the other hand, MUC5AC protein levels were several-fold higher in cells treated with IL-13 than in control cells (P < 0.001, Figure 4).
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Figure 4. MUC5AC protein levels in IL-4–treated cells and IL-13–treated cells measured by ELISA. The cells on Day 21 were analyzed. The levels are presented as percent above control. ***P < 0.001, IL-13–treated cells versus control cells or IL-4–treated cells.
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Electric Properties
The electric properties of cultured epithelial cells are shown in Table 2. IL-13–treated cells had significantly lower PD and lower R than control cells (P < 0.005) and IL-4–treated cells (P < 0.05). However, there were no significant differences of Isc between these three groups; the resistances were too low to measure Isc in some tissues of IL-13–treated epithelial cells.
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Discussion
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In this study, we have found that human recombinant IL-13, but not IL-4, causes a marked goblet cell differentiation in primary cultures of guinea pig tracheal epithelium. Theoretically, both IL-13 and IL-4 bind to IL-4R, activate STAT 6 signaling, and induce goblet cell hyperplasia/metaplasia in vivo (20–22). However, there has been little evidence that these cytokines increase mucin secretion in vitro. In fact, IL-4 inhibits MUC5AC gene expression in primary human bronchial epithelial cells (8). Also, neither IL-4 nor IL-13 increase MUC5AC gene expression in NCI-H292 cells (9, 10). However, these experiments were conducted with short-term incubation (maximally 48 h) with the cytokines. In the present study, we focused on epithelial differentiation in vitro, using primary cultures from the air–liquid interface system. In general, primary cultured cells form a confluent monolayer under immersed conditions within 7 d after being seeded, and progressively differentiate, forming a polarized mucociliary epithelium between Day 14 and Day 21 under air–liquid interface conditions (23). Therefore, the cells were incubated for 2 wk with IL-4 or IL-13 after achieving the confluence at Day 7 after plating.
In a previous report by Adler and coworkers, air–liquid interface cultures of guinea pig cells contained 1/3 goblet cells at control levels (12). However, our control cells rarely showed goblet cells morphologically (Figure 2A, Table 1). This discrepancy is uncertain, but this could be due to different methods, such as medium composition. Similarly, in previous reports, our defined medium induced ciliated cell differentiation, but failed to induce goblet cell differentiation morphologically in canine and bovine culture of tracheal epithelial cells (13, 17).
In this study, we found that IL-13 caused marked goblet cell differentiation and increased MUC5AC protein levels, whereas IL-4 failed to induce goblet cell differentiation and did not increase MUC5AC protein levels. Therefore, IL-4 and IL-13 might play different roles in airway epithelial differentiation. Indeed, this phenomenon may be supported by in vivo studies as follows. Cohn and colleagues (2) reported that goblet cell metaplasia could be achieved even without IL-4, in ovalbumin (OVA)-sensitized, IL-4-/- Th2 cell–adopted mice after challenge with OVA and TNF-, showing that IL-4 is not necessary for mucus production in asthma. Further, McKenzie and coworkers (24) reported that IL-13-/- mice, but not IL-4-/- mice, failed to generate the goblet cell hyperplasia that normally occurs coincident with worm expulsion, suggesting that IL-13 is more critical than IL-4 for mucus production in allergic models or worm infection.
Shim and colleagues reported that IL-13 induced MUC5AC production via EGFR with neutrophil-dependent mechanism in vivo (25). However, our data showed that IL-13 directly produced MUC5AC protein in the absence of neutrophils. As EGFR is known to be a key molecule involved in MUC5AC protein expression of mucous cells (19), further studies are needed to elucidate whether IL-13–induced MUC5AC production is mediated via EGF-receptor in vitro.
The cells treated with IL-13 demonstrated low PD and low resistance, suggesting leaky epithelia. Because these cells consisted of a large number of goblet cells, low resistance might reflect the properties of goblet cell tight junction. Indeed, using freeze-fracture replicas in rat small intestine, goblet cells had fewer strands and less depth of tight junctions that reflect high ionic permeability and low resistance compared with absorptive cells (26). Furthermore, one recent report shows that IL-13 downregulates cytoskeletal components, and impairs lateral cell contact in human nasal epithelial cells (27). Thus, low resistance in IL-13–treated cells might be caused by the disturbance of cytoskeletal components. Increase in epithelial permeability is a feature of asthma. Therefore, IL-13 might be associated with this phenomenon.
In addition to increasing the number of mucous cells, we demonstrated that IL-13 reduced the numbers of ciliated cells (Table 1). This is coincident with a recent report by Laoukili and coworkers concerning the alternation of mucociliary differentiation by IL-13 in human nasal epithelial cells, although their system uses rotary shaking to form epithelial spheroid for epithelial differentiation (27). More mucus and fewer cilia induced by IL-13 might be associated with the impairment of mucociliary clearance seen in asthma. We also demonstrated that the cells on Day 7 were undifferentiated with no ciliated cells (Figure 2A), suggesting that IL-13 induces goblet cell differentiation derived from undifferentiated cells rather than conversion of ciliated to goblet cells. A very high purity of mature goblet cells was obtained with IL-13 treatment in vitro. Therefore, cell treated with IL-13 could be a useful model for studies of goblet cell function such as exocytosis of mucus.
In conclusion, IL-13 but not IL-4 caused goblet cell differentiation, along with less ciliated differentiation in primary cultures of guinea pig tracheal epithelium. IL-13 may thus be an important therapeutic target for goblet cell hyperplasia/metaplasia in asthma.
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Acknowledgments
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The authors thank Masayuki Shino for his excellent technique of electron microscopy.
Received in original form July 26, 2001
Received in final form June 17, 2002
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P. V. Beum, H. Basma, D. R. Bastola, and P.-W. Cheng
Mucin biosynthesis: upregulation of core 2 {beta}1,6 N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line
Am J Physiol Lung Cell Mol Physiol,
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H. Yoshisue, S. M. Puddicombe, S. J. Wilson, H. M. Haitchi, R. M. Powell, D. I. Wilson, A. Pandit, A. E. Berger, D. E. Davies, S. T. Holgate, et al.
Characterization of Ciliated Bronchial Epithelium 1, a Ciliated Cell-Associated Gene Induced During Mucociliary Differentiation
Am. J. Respir. Cell Mol. Biol.,
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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;
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Y. Chen, P. Thai, Y.-H. Zhao, Y.-S. Ho, M. M. DeSouza, and R. Wu
Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop
J. Biol. Chem.,
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Copyright © 2002 American Thoracic Society.
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Abstract
Introduction
