Abstract
Chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis are characterized by persistent airway inflammation and the overproduction of mucus in airways. So-called “goblet (mucous) cell metaplasia/hyperplasia” is the pathologic feature in these diseased airways, in which the normal mucociliary epithelium is replaced by goblet/mucous cells. The nature of the goblet/mucous cell population which arises in these diseased airways is unknown. Our recent studies have shown that trans-differentiation of surface epithelial cells occurs so that they express the submucosal gland-type mucin gene, MUC5B, in addition to a general elevation of all mucin gene products in surface epithelial cells as well as in the submucosal area. In contrast to MUC5B, the surface type of mucin gene, MUC5AC, is restrictedly expressed in the surface epithelium. Using a panel of cytokines—interleukin (IL)-1α, -1β, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -15, -16, -17, -18, and -19, and tumor necrosis factor-α—we have found to our surprise that only IL-6 and -7 can directly stimulate both MUC5AC and MUC5B expression in well-differentiated and polarized primary human airway epithelial cell cultures. Other cytokines, such as the Th2 type IL-4, -5, -9, and -13, cannot. Inhibitor and signaling transduction studies revealed the presence of an IL-6 paracrine/autocrine loop and the dependence on extracellular signal-regulated kinase signaling activation in IL-17-stimulated mucin gene expression. Further studies are needed to connect cytokine-based mucin gene expression and the trans-differentiation phenomenon in airway diseases.