title: Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-kappaB-dependent signaling pathway.
abstract: 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-kappaB-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-1alpha, 1beta, 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-1alpha, 1beta, 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-kappaB activation, suggesting a MEK/NF-kappaB-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-kappaB-based transcriptional mechanisms, respectively.
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Kao
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.forename: Philip
authors.initials: P
authors.lastname: Thai
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Wachi
authors.forename: Christy
authors.initials: C
authors.lastname: Kim
authors.forename: Lucinda
authors.initials: L
authors.lastname: Tam
authors.forename: Reen
authors.initials: R
authors.lastname: Wu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000235:genetics*; D016207:Cytokines / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000494:pharmacology*; D053613:Janus Kinase 1; D007700:Kinetics; D019402:Macrophage Inflammatory Proteins / Q000235:genetics*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D023083:beta-Defensins / Q000096:biosynthesis / Q000494:pharmacology
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D016207:Cytokines; C106641:DEFB4A protein, human; D018076:DNA, Complementary; D020381:Interleukin-17; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D023083:beta-Defensins; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases