Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-κB-dependent signaling pathway

Cheng Yuan Kao, Fei Huang, Yin Chen, Phillip Thai, Shinichiro Wachi, Christy Kim, Lucinda Tam, Reen Wu

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

CCL20, like human β-defensin (hBD)-2, is a potent chemoattractant for CCR6-positive immature dendritic cells and T cells in addition to recently found antimicrobial activities. We previously demonstrated that IL-17 is the most potent cytokine to induce an apical secretion and expression of hBD-2 by human airway epithelial cells, and the induction is JAK/NF-κB-dependent. Similar to hBD-2, IL-17 also induced CCL20 expression, but the nature of the induction has not been elucidated. Compared with a panel of cytoldnes (DL-1α, 1β, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 16, 18, IFN-γ, GM-CSF, and TNF-α), IL-17 was as potent as IL-1α, 1β, and TNF-α, with a time- and dose-dependent phenomenon in stimulating CCL20 expression in both well-differentiated primary human and mouse airway epithelial cell culture systems. The stimulation was largely dependent on the treatment of polarized epithelial cultures from the basolateral side with IL-17, achieving an estimated 4- to 10-fold stimulation at both message and protein levels. More than 90% of induced CCL20 secretion was toward the basolateral compartment (23.02 ± 1.11 ng/chamber/day/basolateral vs 1.82 ± 0.82 ng/chamber/day/apical). Actinomycin D experiments revealed that enhanced expression did not occur at mRNA stability. Inhibitor studies showed that enhanced expression was insensitive to inhibitors of JAK/STAT, p38, JNK, and PI3K signaling pathways, but sensitive to inhibitors of MEK1/2 and NF-κB activation, suggesting a MEK/NF-κB-based mechanism. These results suggest that IL-17 can coordinately up-regulate both hBD-2 and CCL20 expressions in airways through differentially JAK-dependent and -independent activations of NF-κB-based transcriptional mechanisms, respectively.

Original languageEnglish (US)
Pages (from-to)6676-6685
Number of pages10
JournalJournal of Immunology
Volume175
Issue number10
StatePublished - Nov 15 2005

ASJC Scopus subject areas

  • Immunology

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