Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways

Abstract

To address the complex chronic effector properties of interleukin (IL)-10, we generated transgenic mice in which IL-10 was overexpressed in the lung. In these mice, IL-10 inhibited endotoxin-induced tumor necrosis factor production and neutrophil accumulation. IL-10 also caused mucus metaplasia, B and T cell-rich inflammation, and subepithelial fibrosis and augmented the levels of mRNA encoding Gob-5, mucins, and IL-13. In mice bred to have null mutations of IL-13, IL-4R␣, or STAT-6, transgenic IL-10 did not induce mucus metaplasia but did induce inflammation and fibrosis. IL-10 was also a critical mucin regulator of virus-induced mucus metaplasia. Thus, IL-10, although inhibiting lipopolysaccharide-induced inflammation, also causes mucus metaplasia, tissue inflammation, and airway fibrosis. These responses are mediated by multiple mechanisms with mucus metaplasia being dependent on and the inflammation and fibrosis being independent of an IL-13/ IL-4R␣/STAT-6 activation pathway.

Esophageal Remodeling Develops as a Consequence of Tissue Specific IL-5-Induced Eosinophilia

“…It is noteworthy that T helper cell type-2 cytokines are strongly implicated in tissue remodeling and fibrosis in other tissues. [39][40][41] In conclusion, our study demonstrates that eosinophil recruitment to the esophagus is associated with tissue remodeling. First, we show impressive collagen accumulation in the epithelial and subepithelial mucosa of esophageal biopsy specimens from human EE patients.…”

Acellular Pertussis Vaccine Protects against Exacerbation of Allergic Asthma Due toBordetella pertussisin a Murine Model

“…Although IL-10 can act as an immune regulator, our findings suggest that IL-10 has broader functions that may contribute to inflammatory disease (8,13). This may be through direct effects on the smooth muscle in damaged airways (13) or indirectly via induction of IL-13 (25). Although the Pa used in this study enhanced the levels of IL-10 and IL-13 production in response to the sensitizing antigen, the influences of these cytokines appear to be the greatest in the context of the widespread airway epithelial damage that occurs during breakdown of the epithelial-mesenchymal unit (20).…”

“…Our findings of elevated IL-10 levels in BALF specimens support this observation. However, it has been demonstrated recently (25) that IL-10 can induce IL-13 expression in vivo and that this is responsible for the mucus, but not the inflammatory or fibrotic effects, observed in the airways of allergen-sensitized animals. In the present study, we show that Pa immunization prior to OVA sensitization significantly increases both IL-10 and IL-13 levels at the systemic and local levels (Fig.…”

Whole-cell pertussis vaccine protects against Bordetella pertussis exacerbation of allergic asthma

“…It predicts that infections prevent the in- 50 duction of allergen-specific Th2 cells through antagonism or 51 the induction of regulatory T-cells, particularly during neona-52 elled by respiratory challenge of mice, which correlates well 72 to responses in humans [22].…”