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See detailTransforming Growth Factor-beta and Interleukin-1beta Signaling Pathways Converge on the Chemokine CCL20 Promoter.
Brand, Oliver J.; Somanath, Sangeeta; Moermans, Catherine ULiege et al

in Journal of Biological Chemistry (2015), 290(23), 14717-28

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 ... [more ▼]

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. [less ▲]

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