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*
Division of Clinical Immunology and Allergy, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224; and
Department of Pharmacology, SmithKline Beecham, King of Prussia, PA 19406
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-
alone or
in combination with IFN-
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-
compared with RANTES mRNA. IL-4 and IFN- had selective effects on
chemokine expression; IL-4 selectively up-regulated the expression of
eotaxin and MCP-4 and potentiated TNF--induced eotaxin, while
IFN- markedly potentiated only the TNF--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.
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