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 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-alpha alone or in combination with IFN-gamma 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-alpha compared with RANTES mRNA. IL-4 and IFN-gamma had selective effects on chemokine expression; IL-4 selectively up-regulated the expression of eotaxin and MCP-4 and potentiated TNF-alpha-induced eotaxin, while IFN-gamma markedly potentiated only the TNF-alpha-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.
Stellato
C
C
Division of Clinical Immunology and Allergy, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA. stellato@welch.jhu.edu
Matsukura
S
S
Fal
A
A
White
J
J
Beck
L A
LA
Proud
D
D
Schleimer
R P
RP
D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D002631:Chemotactic Factors, Eosinophil / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D005938:Glucocorticoids; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007700:Kinetics; D018945:Monocyte Chemoattractant Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; C515456:CCL11 protein, human; C099677:CCL13 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D005938:Glucocorticoids; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D019819:Budesonide; D007371:Interferon-gamma