Article (Scientific journals)
Transforming Growth Factor-beta and Interleukin-1beta Signaling Pathways Converge on the Chemokine CCL20 Promoter.
Brand, Oliver J.; Somanath, Sangeeta; Moermans, Catherine et al.
2015In Journal of Biological Chemistry, 290 (23), p. 14717-28
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Keywords :
Animals; Base Sequence; Cells, Cultured; Chemokine CCL20/genetics; Fibroblasts/immunology/metabolism; Gene Expression Regulation; Humans; Interleukin-1beta/immunology; Lung/cytology; Mice; Mice, Inbred C57BL; NF-kappa B/immunology; Response Elements; Signal Transduction; Transforming Growth Factor beta/immunology; TGF-beta; chemokine; inflammation; integrin; transcription
Abstract :
[en] CCL20 is the only chemokine ligand for the chemokine receptor CCR6, which is expressed by the critical antigen presenting cells, dendritic cells. Increased expression of CCL20 is likely involved in the increased recruitment of dendritic cells observed in fibroinflammatory diseases such as chronic obstructive pulmonary disease (COPD). CCL20 expression is increased by the proinflammatory cytokine IL-1beta. We have determined that IL-1beta-dependent CCL20 expression is also dependent on the multifunctional cytokine TGF-beta. TGF-beta is expressed in a latent form that must be activated to function, and activation is achieved through binding to the integrin alphavbeta8 (itgb8). Here we confirm correlative increases in alphavbeta8 and IL-1beta with CCL20 protein in lung parenchymal lysates of a large cohort of COPD patients. How IL-1beta- and alphavbeta8-mediated TGF-beta activation conspire to increase fibroblast CCL20 expression remains unknown, because these pathways have not been shown to directly interact. We evaluate the 5'-flanking region of CCL20 to determine that IL-1beta-driven CCL20 expression is dependent on alphavbeta8-mediated activation of TGF-beta. We identify a TGF-beta-responsive element (i.e. SMAD) located on an upstream enhancer of the human CCL20 promoter required for efficient IL-1beta-dependent CCL20 expression. By chromatin immunoprecipitation, this upstream enhancer complexes with the p50 subunit of NF-kappaB on a NF-kappaB-binding element close to the transcriptional start site of CCL20. These interactions are confirmed by electromobility shift assays in nuclear extracts from human lung fibroblasts. These data define a mechanism by which alphavbeta8-dependent activation of TGF-beta regulates IL-1beta-dependent CCL20 expression in COPD.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Brand, Oliver J.
Somanath, Sangeeta
Moermans, Catherine  ;  Université de Liège - ULiège
Yanagisawa, Haruhiko
Hashimoto, Mitsuo
Cambier, Stephanie
Markovics, Jennifer
Bondesson, Andrew J.
Hill, Arthur
Jablons, David
Wolters, Paul
Lou, Jianlong
Marks, James D.
Baron, Jody L.
Nishimura, Stephen L.
More authors (5 more) Less
Language :
English
Title :
Transforming Growth Factor-beta and Interleukin-1beta Signaling Pathways Converge on the Chemokine CCL20 Promoter.
Publication date :
June 2015
Journal title :
Journal of Biological Chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, United States - Maryland
Volume :
290
Issue :
23
Pages :
14717-28
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Available on ORBi :
since 11 February 2019

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