title: CCL27 expression is regulated by both p38 MAPK and IKKβ signalling pathways.
abstract: The skin-specific chemokine CCL27 is believed to play a pivotal role in establishing the inflammatory infiltrate characteristic for common inflammatory skin diseases. Through binding to the chemokine receptor 10 (CCR10), CCL27 mediates inflammation by promoting lymphocyte migration into the skin. Little is known about the regulation of CCL27 gene expression. The purpose of our study was to investigate the regulation of the IL-1β-induced CCL27 gene expression in normal human keratinocytes (NHEK). Preincubation of NHEK with the inhibitory κB (IκB) kinase (IKK) inhibitor, SC-514, or the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB202190, revealed a profound reduction in both CCL27 mRNA and CCL27 protein expression indicating the significance of these pathways in the regulation of CCL27 expression. Furthermore, the impact of inhibitors of mitogen- and stress-activated kinase 1 (MSK1) or the mitogen-activated protein kinase-interacting kinases (Mnk1+2), downstream kinases of p38 MAPK, on IL-1β-induced CCL27 expression in NHEK were investigated. We identified seven NF-κB binding elements upstream from the CCL27 gene start codon using electrophoretic mobility shift assay (EMSA). Supershift analyses demonstrated the involvement of the p50/p65 NF-κB heterodimer. We conclude that IL-1β-induced CCL27 gene expression in NHEK is regulated through the p38 MAPK/MSK1/Mnk1+2 as well as the IKKβ/NF-κB signalling pathways.
authors: Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, Aarhus C, Denmark. jette.lindorff.riis@ki.au.dk
authors: Jette Lindorff
authors: JL
authors: Riis
authors: Claus
authors: C
authors: Johansen
authors: Christian
authors: C
authors: Vestergaard
authors: Kristian
authors: K
authors: Otkjaer
authors: Knud
authors: K
authors: Kragballe
authors: Lars
authors: L
authors: Iversen
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000378:metabolism; D054425:Chemokine CCL27 / Q000235:genetics* / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D000078404:Epidermal Cells; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C492276:CCL27 protein, human; D027682:Cation Transport Proteins; D054425:Chemokine CCL27; D007093:Imidazoles; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C477523:SC 514; D013876:Thiophenes; D051996:Transcription Factor RelA; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole