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

Cristiana Stellato, Satoshi Matsukura, Andrzej Fal, John White, Lisa A. Beck, David Proud, Robert P. Schleimer

Research output: Contribution to journalArticlepeer-review

Abstract

Airway epithelial cells are a rich source of eosinophil-selective C-C chemokines. We investigated whether cytokines and the topical glucocorticoid budesonide differentially regulate RANTES, monocyte chemoattractant protein-4 (MCP-4), and eotaxin mRNA and protein expression in the human bronchial epithelial cell line BEAS-2B and in primary human bronchial epithelial cells by Northern blot analysis and ELISAs. Eotaxin and MCP-4 mRNA expression induced by TNF-α alone or in combination with IFN-γ was near-maximal after 1 h, peaked at 4 and 8 h, respectively, remained unchanged up to 24 h, and was protein synthesis independent. In contrast, RANTES mRNA was detectable 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 100- fold greater sensitivity to TNF-α compared with RANTES mRNA. IL-4 and IFN-γ had selective effects on chemokine expression; IL-4 selectively up-regulated the expression of eotaxin and MCP-4 and potentiated TNF-α-induced eotaxin, while IFN-γ markedly potentiated only the TNF-α-induced expression of RANTES. Although budesonide inhibited the expression of chemokine mRNA to a variable extent, it effectively inhibited production of eotaxin and RANTES protein. Budesonide inhibited both RANTES- and eotaxin promoter-driven reporter gene activity. Budesonide also selectively accelerated 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 chemokine expression through multiple mechanisms of action.

Original languageEnglish (US)
Pages (from-to)5624-5632
Number of pages9
JournalJournal of Immunology
Volume163
Issue number10
StatePublished - Nov 15 1999

ASJC Scopus subject areas

  • Immunology

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