Th1- and Th2-type cytokines regulate the expression and production of eotaxin and RANTES by human lung fibroblasts

Eosinophils (Eos) and fibroblasts are known to play a major role in the pat hogenesis of bronchial asthma and fibrotic lung disease, Therefore, we inve stigated whether Th1 and Th2 cytokines stimulate the production of Eo-activ ating chemokines by lung fibroblasts. Analyses of the culture supernatant u sing multiple steps of high-performance liquid chromatography demonstrated that interleukin (IL)-4 preferentially stimulates lung fibroblasts to secre te a peak of eosinophil chemotactic activity (ECA) which, upon N-terminal a nalyses, showed similar sequence to eotaxin, whereas interferon (IFN)-gamma had negligible effect on the release of this chemokine. In contrast, tumor necrosis factor (TNF)-alpha stimulated lung fibroblasts to release two pea ks of activity that were found to correspond to eotaxin and regulated on ac tivation, normal T cells expressed and secreted (RANTES), respectively. Int erestingly, IL-4 synergized with TNF-alpha to increase greatly the producti on of three biochemically distinct eotaxin forms. In contrast, IFN-gamma sy nergized with TNF-alpha to increase RANTES production. Neither IL-2, IL-5, IL-6 nor IL-10 had an effect on lung fibroblasts' capacity to express or re lease eotaxin and RANTES. Upon appropriate cytokine stimulation, lung fibro blasts were also found to express messenger RNA for monocyte chemotactic pr otein (MCP)-3 and MCP-4 but not eotaxin-2. However, no ECA like MCP-3 or MC P-4 was detected. These observations suggest that the release of Th1 or Th2 cytokines in the lung tissue polarizes lung fibroblasts to produce either RANTES or eotaxin as major Eo attractants.