Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells

Abstract

A hallmark of asthma is mucin overproduction, a condition that contributes to airway obstruction. The events responsible for mucin overproduction are not known but are thought to be associated with mediators of chronic inflammation. Others have shown that T-helper 2 (Th2) lymphocytes are required for mucous cell metaplasia, which then leads to mucin overproduction in animal models of allergy. We hypothesized that Th2 cell mediators are present in asthmatic airway fluid and directly stimulate mucin synthesis in airway epithelial cells. Results in cultured airway epithelial cells showed that samples of asthmatic fluid stimulated mucin (MUC5AC) synthesis severalfold more potently than non-asthmatic fluid. Consistent with this, lavage fluid from the airways of allergen-challenged dogs stimulated mucin synthesis severalfold more potently than that from non-allergen-challenged dogs. Fractionation of dog samples revealed 2 active fractions at <10 kDa and 30-100 kDa. Th2 cytokines in these molecular weight ranges are IL-9 (36 kDa), IL-5 (56 kDa), and IL-13 (10 kDa). Antibody blockade of ligand-receptor interaction for IL-9 (but not IL-5 or IL-13) inhibited mucin stimulation by dog airway fluid. Furthermore, recombinant IL-9, but not IL-5 or IL-13, stimulated mucin synthesis. These results indicate that IL-9 may account for as much as 50-60% of the mucin-stimulating activity of lung fluids in allergic airway disease.

Effect of TH2 cytokines and interferon gamma on beat frequency of human respiratory cilia

“…Treatment with substances targeting IL-5 reduces exacerbation rate and sputum eosinophilia and increases the quality of life in clinical trials with patients having refractory eosinophilic asthma (34). IL-9 has effects on ciliated cell differentiation and mucus hypersecretion (16,35,36). Although IL-5 and IL-9 are relevant cytokines in asthma pathophysiology their influence on CBF is not yet known.…”

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).…”

“…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). IL-9's ability to directly induce MUC5AC gene expression on airway epithelial cells is controversial (92,97).…”

“…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). IL-9's ability to directly induce MUC5AC gene expression on airway epithelial cells is controversial (92,97). Under one scenario, IL-9's ability to directly induce mucous cells in culture may require a coexisting degree of injury and repair (98).…”

Les lymphocytes Th9

“…Les Th9 semblent également être impliqués dans la maladie asthmatique. En effet, l'IL-9 stimule la production du mucus, l'infiltration de leucocytes et la production d'IgE par les lymphocytes B [20]. Elle active également la production d'histamine par les mastocytes [21] leur conférant un rôle dans l'allergie chronique.…”