Interleukin-9 Upregulates Mucus Expression in the Airways

Abstract

Interleukin (IL)-9 has recently been shown to play an important role in allergic disease because its expression is strongly associated with the degree of airway responsiveness and the asthmatic-like phenotype. IL-9 is a pleiotropic cytokine that is active on many cell types involved in the allergic immune response. Mucus hypersecretion is a clinical feature of chronic airway diseases; however, the mechanisms underlying the induction of mucin are poorly understood. In this report, we show that IL-9 regulates the expression of a subset of mucin genes in lung cells both in vivo and in vitro. In vivo, the constitutive expression of IL-9 in transgenic mice results in elevated MUC2 and MUC5AC gene expression in airway epithelial cells and periodic acid-Schiff-positive staining (reflecting mucous glycogenates). Similar results were observed in C57BL/6J mice after IL-9 intratracheal instillation. In contrast, instillation of the T helper 1-associated cytokine interferon gamma failed to induce mucin production. In vitro, our studies showed that IL-9 also induces expression of MUC2 and MUC5AC in human primary lung cultures and in the human muccoepidermoid NCI-H292 cell line, indicating a direct effect of IL-9 on inducing mucin expression in these cells. Altogether, these results suggest that upregulation of mucin by IL-9 might contribute to the pathogenesis of human inflammatory airway disorders, such as asthma. These data extend the role of the biologic processes that IL-9 has on regulating the many clinical features of asthma and further supports the IL-9 pathway as a key mediator of the asthmatic response.

Regulation of Airway Mucin Gene Expression

“…This observation is consistent with the close association of mucous cell hyperplasia/metaplasia seen in allergic airway diseases such as asthma. IL-9 induces MUC5AC/Muc5ac both in vitro and in vivo (92)(93)(94)(95)(96), although few data exist as to the intracellular mechanisms of its action. IL-9's effect on MUC5AC may be mediated through IL-13 (95,96), although other studies dispute the role of IL-13 (92,94).…”

Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop

“…IL-9 has also been shown to have the ability to stimulate mucous cell hyperplasia in vivo (35) as well as mucin gene expression in vitro (36,37). However, gene knockout mice of IL-9 showed that IL-9 was necessary for mucous cell hyperplasia in a granuloma model of disease (38) but not in an allergic asthma model (39).…”

“…However, gene knockout mice of IL-9 showed that IL-9 was necessary for mucous cell hyperplasia in a granuloma model of disease (38) but not in an allergic asthma model (39). In cell cultures, stimulation of MUC5AC by IL-9 could be seen (36,37) but the cells used were undifferentiated TBE cells or cancerous cell lines. To further define the roles of cytokines in mucin gene expression, we used well differentiated primary cultures of human tracheobronchial epithelial (TBE) cells (40,41) to determine which cytokines can stimulate MUC5AC and MUC5B expression.…”

IL-9 Promotes IL-13-Dependent Paneth Cell Hyperplasia and Up-Regulation of Innate Immunity Mediators in Intestinal Mucosa

“…Such conditions can be mimicked by overexpression of TH2 cytokines such as IL-9 and IL-13 in the lungs. Indeed, IL-9 transgenic (Tg) 3 and IL-13 Tg mice show increased mucus production by lung goblet cells (1,2) and airway hyperresponsiveness (2)(3)(4). Further studies of IL-9 Tg mice showed that IL-9 activities on lung epithelial cells are actually mediated by up-regulation of IL-13 expression by T and mast cells (5)(6)(7).…”