Cytokines modulate cilomilast response in lung fibroblasts

Fibroblasts, as a major source of extracellular interstitial connective tissue matrix, play an important role in wound healing and the development of fibrosis. The phosphodiesterase (PDE) 4 inhibitor cilomilast inhibits fibroblast chemotaxis and fibroblast-mediated gel contraction. Using the Boyden blindwell chamber chemotaxis assay and the type I collagen gel contraction model, this study investigated whether specific cytokines modulate cilomilastʹs inhibitory effect through regulation of endogenous PGE2 production. Human recombinant IL-1β stimulated PGE2 production and shifted the cilomilast concentration–dependence curve to the left in both assay systems, indicating increased sensitivity to cilomilast. In contrast, human recombinant IL-4 inhibited PGE2 production and shifted the cilomilast concentration–dependence curve to the right in both systems. In summary, the inhibitory effect of cilomilast on fibroblast migration and collagen gel contraction is modulated by IL-1β and IL-4 through regulation of PGE2 production.