Der p, IL-4, and TGF-β Cooperatively Induce EGFR-Dependent TARC Expression in Airway Epithelium

Abstract

Thymus and Activation-Regulated Chemokine (TARC) may be critical in Th2 cell recruitment in allergic inflammation; however, the mechanisms of allergen-induced TARC release are unclear. Since airway epithelium is the first line of defense to inhaled allergens, we questioned whether house dust mite allergen (Der p) can induce TARC expression in bronchial epithelial cells, how this is regulated at the molecular level, and if micro-environmental cytokines augment this effect. We examined the effects of Der p and the cytokines IL-4 and TGF-beta on TARC expression in 16HBE cells and primary bronchial asthma epithelium. Real-time PCR and immunofluorescence demonstrated that Der p induces TARC expression in bronchial epithelium. Supernatants from Der p-stimulated 16HBE cells were able to induce TARC-dependent T cell trafficking. IL-4 and TGF-beta cooperatively enhanced Der p-induced TARC expression in 16HBE cells. Specific inhibitors, immunodetection, and gel-shifts revealed that these effects are mediated by phosphorylation of the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK) signaling and subsequent nuclear factor (NF)-kappaB activation. A Disintegrin And Metalloproteinase (ADAM), a family of proteins involved in shedding of various growth factors, was shown to be responsible for EGFR activation. The increase in TARC production by direct interaction of Der p with the bronchial epithelium may be an important initial step in the generation of allergic inflammation, which is further potentiated by micro-environmental cytokines. Interference with ADAM or EGFR activity may be a novel promising target to prevent TARC release and subsequent allergic inflammation.

Transglutaminase II/MicroRNA-218/-181a Loop Regulates Positive Feedback Relationship between Allergic Inflammation and Tumor Metastasis

“…EGFR signaling is activated by asthma-related cytokines and inflammation (40). House dust mite allergen (Der p) increases the secretion of thymus and activation-regulated chemokine in an EGFR-dependent manner, resulting in allergic inflammation (41). It is probable that cross-talk between EGFR and Fc⑀RI is necessary for allergic inflammation.…”

Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

“…Airway epithelial cells induce migration of Th1 cells into mucosae via production of the CXCR3 ligands, CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC), and induce migration of Th2 cells via production of the CCR8 ligand CCL1 (I-309) and the CCR4 ligands CCL17 (TARC) and CCL22 (MDC) (Figure 1) [42][43][44][45][46][47]. CXCR3 is expressed on activated T cells, predominantly of the Th1 phenotype, as well as on NK cells and a subset of circulating memory CD4 + and CD8 + T cells.…”

“…CCR4, a receptor for the epithelial products CCL17 and CCL22, is also expressed on Th2 cells. CCL17 production is induced by IL-4, IL-13, TGF-β and the house dust mite allergen Der p in airway epithelial cells [46,47]. In addition, synergistic induction of CCL17 is induced by the combination of TNF with either Th2 cytokines, TGF-β or Der p antigen.…”

The Effect of Wasabi Rhizome Extract on Atopic Dermatitis-Like Symptoms in HR-1 Hairless Mice

“…Uto et al reported that 6-MSITC inhibited MAPK signaling pathways in inflammation (19,27). It has also been reported that expressions of TARC and eotaxin are controlled via MAPK signaling pathways (28,29). 6-MSITC might adjust chemical mediators through MAPK signaling pathways.…”