Differential regulation of epithelial-derived C-C chemokine expression by IL-4 and the glucocorticoid budesonide

Airway epithelial cells are a rich source of eosinophil-selective C-C chemo kines, We investigated whether cytokines and the topical glucocorticoid bud esonide differentially regulate RANTEs, monocyte chemoattractant protein-4 (MCP-4), and cotaxin mRNA and protein expression in the human bronchial epi thelial cell line BEAS-2B and in primary human bronchial epithelial cells b y Northern blot analysis and ELISAs. Eotaxin and MCP-4 mRNA expression indu ced by TNF-alpha alone or in combination with IFN-gamma vas near-maximal af ter 1 h, peaked at 3 and 8 h, respectively, remained unchanged up to 24 h, and was protein synthesis independent. In contrast, RANTES mRNA was detecta ble only after 2 h and slowly increased to a peak at 24 h, and was protein synthesis dependent. Induction of eotaxin and MCP-4 mRNA showed a 10- to 10 0-fold greater sensitivity to TNF-alpha compared with RANTES mRNA. IL-4 and IFN-gamma had selective effects on chemokine expression; IL-4 selectivity up-regulated the expression of eotaxin and MCP-4 and potentiated TNF-alpha- induced eotaxin, while IFN-gamma markedly potentiated only the TNF-alpha in duced expression of RANTES. Although budesonide inhibited the expression of chemokine mRNA to a variable extent, it effectively inhibited production o f eotaxin and RANTES protein. Budesonide inhibited bath RANTES- and eotaxin promoter-driven reporter gene activity. Budesonide also selectively accele rated the decay of eotaxin and MCP-4 mRNA. These results point to IL-4 as a possible mediator by which Th2 cells may induce selective production of C- C chemokines from epithelium and indicate that glucocorticoid inhibit chemo kine expression through multiple mechanisms of action.