Interleukin-17A and Interleukin-19 in Regulating Airway Epithelial Immunity

Results from recent studies suggest that in addition to the barrier function, airway epithelial cells (AECs) also actively participating in airway immune response. We previously demonstrated that IL-17A is a potent inducer of human beta-defensin (hBD) 2 and CCL20 expression in well-differentiated human AECs. In addition to the anti-microbial activity, both hBD2 and CCL20 are principal chemotactic ligands of CCR6, which is expressed by dendritic cells (DC) and T lymphocytes. To further explore the chemotactic significance of IL-17A in the mouse system, we conducted studies using primary mouse AECs and Cc10-Il17 transgenic animals, which display airway overexpression of IL-17A. We found that mouse AECs expressed elevated mCcl20 in response to mIL-17A in an NF-kappaB-dependent manner. Conditioned media from mIL-17A-treated mouse AECs stimulated the migration of CCR6-positive bone marrow-derived DC in vitro; this chemotactic activity was blocked by an anti-CCL20 neutralizing antibody. In Cc10-Il17 transgenic mice, we detected elevated mCcl20 in the lung and an increased number of CCR6-positive DCs in bronchoalveolar lavage fluid. These mice also display increased mucin production in their lungs compared to wild-type mice. Blocking the migration of CCR6-expressing cells in vivo by anti-CCR6 or anti-CCL20 antibody lowered mucin production in the airways, suggesting a functional role of IL-17A/CCL20 in regulating CCR6-positive DC migration and mucous cell metaplasia. IL-17A also induces the expression of IL-19, a proinflammatory cytokine in the IL-10 cytokine family, in human AECs. We have shown the association of IL-19 with asthma and that AECs were one of the potential sources of IL-19 in the disease. Using well-differentiated primary mouse AECs grown under air-liquid interface conditions, we demonstrated that Th2 cytokines such as IL-4 and IL-13 could induce Il19 expression. In the OVA mouse asthma model, Il19 expression was elevated in asthmatic lung tissue at the early stage. This elevation was observed in airway epithelial cells but not alveolar macrophages. An increase was only observed for IL-19 and not other IL-20 subfamily members, such as IL-20, IL-22, and IL-24. We further demonstrated that IL-19 could stimulate in vitro Th2 cell lineage differentiation of naive T cells when added initially to the polarizing medium. These results demonstrate that IL-19 produced by airway epithelial cells at the early stage of the asthmatic response may further amplify the Th2 response through promoting T helper cell differentiation.;IL-19 has also been shown to stimulate beta-defensin in keratinocytes, but its potential to induce defensin expression in the airways has not been characterized. Here we report that IL-19 is able to induce hBD gene ( DEFB4) expression in human airway epithelial cell line HBE-1, as well as primary mouse airway cells. Both STAT1 and STAT3 are required in IL-19-induced DEFB4 although only STAT3 is significantly activated by IL-19 while STAT1 is constantly phosphorylated. STAT5 is also phosphorylated in HBE-1 but does not involve in DEFB4 induction; however knocking down STAT5 appears to alter basal DEFB4 level. In addition to IL-19 we also found other IL-20 subfamily cytokines, including IL-20, -22, -24, and -26, capable of stimulating DEFB4 expression in HBE-1 cells.