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The Journal of Immunology, 2005, 175: 6676-6685.
Copyright © 2005 by The American Association of Immunologists

Up-Regulation of CC Chemokine Ligand 20 Expression in Human Airway Epithelium by IL-17 through a JAK-Independent but MEK/NF-{kappa}B-Dependent Signaling Pathway1

Cheng-Yuan Kao, Fei Huang, Yin Chen, Philip Thai, Shinichiro Wachi, Christy Kim, Lucinda Tam and Reen Wu2

Center for Comparative Respiratory Biology and Medicine, University of California, Davis, CA 95616

CCL20, like human {beta}-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-{kappa}B-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 cytokines (IL-1{alpha}, 1{beta}, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, IFN-{gamma}, GM-CSF, and TNF-{alpha}), IL-17 was as potent as IL-1{alpha}, 1{beta}, and TNF-{alpha}, 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-{kappa}B activation, suggesting a MEK/NF-{kappa}B-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-{kappa}B-based transcriptional mechanisms, respectively.




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