Upstream eventActivation, Epidermal Growth Factor Receptor
Occurrence, Transdifferentiation of ciliated epithelial cells
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
IL13 stimulates transdifferentiation of ciliated epithelial cells to goblet cells through EGFR activation (Tyner et al. 2006), MMP/ADAM (Yoshisue and Hasegawa 2004), p38 MAPK (Fujisawa, et al. 2008) and inhibition of FOXJ1 (Gomperts, et al. 2007). In addition to IL13, IL4 has been shown to act through shared receptor IL4RA to stimulate goblet cell differentiation and inhibit ciliogenesis (Laoukili, et al. 2001). IL4 and IL13 but not IL5 or IL9 have been shown to induce goblet cell metaplasia in mouse trachial epiethelial cells (Fujisawa, et al. 2008).
Evidence Supporting this KER
There is biological plausibility of ciliated cell transdifferentiation to goblet cells as a number of studies have shown a mix of features characteristic of each cell type within a cell (Tyner, et al. 2006, Laoukili, et al. 2001, Gomperts et al. 2007) or fluorescent labeling from ciliated cells detected in goblet cells after differentiation (Turner et al. 2011).
However, ciliated cell transdifferentiation remains controversial in terms of napthalene or sulfur dioxide-induced injury with conflicting reports for lack of transdifferentiation (Rawlins, et al. 2006) and evidence for transdifferentiation (Van Winkle, et al. 1995; Lawson, et al. 2002, Park, et al. 2006).
Include consideration of temporal concordance here
In cultured 3D differentiated human airway epithelial tissue, 50 or 100ng/mL IL13 induced transdifferentiation of ciliated to goblet cells after 3 days, measured by decreased FOXJ1 and loss of ezrin and basal bodies, features of ciliated cells and increase of MUC5AC protein, a marker for goblet cells (Gomperts 2007).
In cultured human bronchial epithelial cells, goblet cells were derived from ciliated cells after 1 ng/mL IL13 treatment for 28-35 days shown by green fluorescent labeling (Turner 2011).
In cultured human bronchial epithelial cells, 20ng/mL IL13 for 14 days increased goblet cell and decreased ciliated cell gene markers, and increased mucus production via MMP/ADAM (Yoshisue 2004). Accompanying increase in EGFR ligand TGFA indicates the EGFR pathway was involved in IL13-induced ciliat to goblet differentiation.
Uncertainties and Inconsistencies
IL13-induced goblet cell increase has been shown to be concentration-dependent in human bronchial epithelial cells with 1ng/ml inducing and 10ng/ml suppressing goblet cell increase (Atherton, et al. 2003), however multiple studies have shown that concentrations from 5-100ng/mL do induce goblet cell hyperplasia, including in human bronchial epithelial cells (Yoshisue 2004).
It has been shown that two weeks but not one week of human nasal epithelial cell differentiation and IL13 treatment showed a decrease in proportion of ciliated cells (shown by glutamylated tubulin protein expression) (Laouikili 2001), however other studies showed that IL13-induced ciliated to goblet cell differentiation were observed in as little as 3-5 days cultured human airway epithelium, mouse tracheal epithelial cells and a Sendai virus mouse model (Gomperts 2007, Fujisawa 2008, Tyner 2006). This difference may be due to the difference in cell types used in these experiments. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge for 48 hours which may be due to insufficient time for OVA-induced IL13 upregulation and subsequent effects (Pardo-Saganta 2013).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
It has been proposed that the effects of IL13 and IL4 on differentiation to goblet cells is concentration-dependent in human bronchial epithelial cells, with 1ng/ml inducing an increase in goblet cell density acting through MAPK and p38 MAPK but not EGFR and 10ng/ml inducing a reduction in goblet cell density (Atherton et al. 2003). Other studies have agreed with this finding, with 1ng/mL IL13 leading to an increase in goblet hyperplasia in human bronchial epitehlial cells (Turner 2011) and 5ng/mL having a lack of effect inducing goblet cell differentiation in nasal epithelial cells (Kim 2002). On the contrary, multiple studies have shown that concentrations from 5-100ng/mL do induce goblet cell hyperplasia in human bronchial epithelial cells, human nasal epithelial cells, cultured human differentiated airway epithelial tissue, cultured guinea pig tracheal epithelium, and mouse tracheal epithelial cells (Yoshisue 2004, Laouikili 2001, Gomperts 2007, Kondo 2002, Fujisawa 2008).
It has also been proposed that two weeks of differentiation is necessary to see the effects (Laouikili 2001) and could explain why differentiation was not observed in a two day OVA-induced murine model (Pardo-Saganta 2013) or seven day human nasal epithelial cell model (Kim 2002). On the contrary, IL13-induced goblet cell metaplasia was also observed in short term experiments of 3-5 days in cultured human airway epithelium, mouse tracheal epithelial cells and a Sendai virus mouse model (Gomperts 2007, Fujisawa 2008, Tyner 2006).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
There are many human studies demonstrating transdifferentiation from ciliated to goblet cells including in 3D human airway epithelial models (Gomperts et al. 2007), human bronchial or nasal epithelial cells in vitro (Yoshisue and Hasegawa 2004, Turner et al. 2011, Laoukili, et al. 2001) and in COPD patients (Tyner, et al. 2006).
Two mouse studies have demonstrated transdifferentiation and goblet metaplasia (Tyner, et al. 2006, Fujisawa, et al. 2008) while another mouse study has shown that ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge (Pardo-Saganta, et al. 2013), however this could be due to the short 48 hour time point which has been noted is not enough time for transdifferentiation (Laoukili, et al. 2001).
Rat studies have demonstrated IL-13 and/or EGFR involvement in goblet cell metaplasia/hyperplasia, however no rat studies have directly measured transdifferentiation of ciliated to goblet cells to our knowledge (Shim 2001, Takeyama 2008).