Expression of IL-4/IL-13 receptors in differentiating human airway epithelial cells

Abstract

and IL-13 elicit several important responses in airway epithelium including chemokine secretion and mucous secretion that may contribute to airway inflammation, cell migration, and differentiation. These cytokines have overlapping but not identical effector profiles likely due to shared subunits in their receptor complexes. These receptors are variably described in epithelial cells, and the relative expression, localization, and function of these receptors in differentiated and repairing epithelial cells are not clear. We examined IL-4/IL-13 receptor expression and localization in primary airway epithelial cells collected from normal human lungs and grown under conditions yielding both undifferentiated and differentiated cells inclusive of basal, goblet, and ciliated cell phenotypes. Gene expression of the IL-4R␣, IL-2R␥c, IL-13R␣1, and IL-13R␣2 receptor subunits increased with differentiation, but different patterns of localization and protein abundance were seen for each subunit based on both differentiation and the cell subtypes present. Increased expression of receptor subunits observed in more differentiated cells was associated with more substantial functional responses to IL-4 stimulation including increased eotaxin-3 expression and accelerated migration after injury. We demonstrate substantial differences in IL-4/IL-13 receptor subunit expression and responsiveness to IL-4 based on the extent of airway epithelial cell differentiation and suggest that these differences may have functional consequences in airway inflammation.interleukin-4; interleukin-13; eotaxin-3; migration THE AIRWAY EPITHELIUM is both a target of inflammatory and physical insults and an effector of ongoing airway inflammation (2,20,31,37,45). As such, it plays a critical role in diseases such as chronic asthma. Epithelial injury leads to release of chemokines such as 8,13), GM-CSF (13, 42), and eotaxin (65) that then stimulate inflammatory cell infiltration. Injury also leads to disordered regulation of submucosal myofibroblasts (19) and subsequent subbasement membrane fibrinogenesis (40). Persistent epithelial injury (31,39,56) is a characteristic part of airway remodeling (9) in asthma.Activated lymphocytes are a prominent feature in asthmatic airways (5,6,32). BAL fluid obtained from asthmatics is enriched in both IL-4 (50) and IL-13 (21, 22) but not IFN-␥ (50), indicating the presence of T helper type 2 (Th2) subclass CD4 ϩ cells. Both IL-4 and IL-13 may stimulate epithelial cells to produce chemokines such as eotaxin-3 (28, 55, 65), GM-CSF (42), 28), and RANTES (17,46) and growth factors such as transforming growth factor-␤ (TGF-␤) (50, 57) and the EGF receptor-binding factor, TGF-␣ (4). Overexpression of either IL-4 or IL-13 in murine airways elicits inflammation, subepithelial fibrosis, and mucous cell metaplasia (49, 67).IL-4 and IL-13 have overlapping but not identical effector profiles likely due to shared subunits in their receptor complexes (43). IL-4 can bind to two distinct receptors: the type I receptor consisting of the...

Upregulated Protein Arginine Methyltransferase 1 by IL-4 Increases Eotaxin-1 Expression in Airway Epithelial Cells and Participates in Antigen-Induced Pulmonary Inflammation in Rats

“…IL-4 leads to the activation of multiple signaling pathways, including Stat6, CREB, NF-kB, and GATA3 (30)(31)(32), which induce eotaxin production. We used the software, TFSEARCH (version 1.3, Web site: http:// www.cbrc.jp/research/db/TFSEARCH.html), to predict the promoter region of PRMT1 and found that STATs, CREB, NF-kB, and GATA3 may combine with the promoter region of PRMT1.…”

Tight junctions in pulmonary epithelia during lung inflammation

“…Although IL-4 and IL-13 show similar effects on TJ in these airway epithelial cell models, depending on the investigated model, they act via different pathways. In Calu3 epithelia, IL-4 is reported to activate an EGFR-dependent MAPK/ERK1/2 pathway [100], whereas in human bronchial cell derived epithelia IL-4 as well as IL-13 act via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway [107], most likely via binding to the same receptor, namely heteromeric IL-13Rα/IL-4Rα receptor [139]. Indeed, both receptor subunits have an overlapping expression pattern in lung epithelia.…”

“…Indeed, both receptor subunits have an overlapping expression pattern in lung epithelia. IL-4Rα as well as IL-13Rα both were detected in human bronchial epithelial cells in vitro and in vivo [4, 46, 129, 133, 139]. IL-13Rα expression levels are increased in bronchial biopsy specimens from asthma patients which probably confers increased bronchial sensitivity to T H 2 cytokines [69].…”

Interleukin-13 Pathway Alterations Impair Invariant Natural Killer T-Cell–Mediated Regulation of Effector T Cells in Type 1 Diabetes

“…Conventional PCR and Sequence Analysis IL-13, IL13Ra1, and IL13Ra2 expression was analyzed by RT-PCR with previously described primers (28)(29)(30). Primers specific for CD3g were forward 59-CCCAATG ACCAGCTCTACCA-39 and reverse 59-GGAACTGAATAGG AGGAGAACAC-39.…”