title: LPS-induced inflammatory response is suppressed by Wnt inhibitors, Dickkopf-1 and LGK974.
abstract: In this study, LPS-induced inflammatory responses in BEAS-2B human bronchial epithelial cells and human umbilical vein endothelial cell (HUVEC)s were found to be prevented by Dickkopf-1 (DKK-1), a secreted Wnt antagonist, and LGK974, a small molecular inhibitor of the Wnt secretion. LPS-induced IκB degradation and NF-κB nuclear translocation as well as the expressions of pro-inflammatory genes including IL-6, IL-8, TNF- α, IL-1β, MCP-1, MMP-9, COX-2 and iNOS, were all suppressed by DKK-1 and LGK974 in a dose-dependent manner. The suppressive effects of LGK974 on NF-κB, IκB, and pro-inflammatory gene expression were rescued by ectopic expression of β-catenin, suggesting that the anti-inflammatory activity of LGK974 is mediated by modulation of the Wnt/β-catenin pathway and not by unrelated side effects. When Wnt recombinant proteins were treated to cells, Wnt3a and Wnt5a significantly induced pro-inflammatory gene expressions, while Wnt7a and Wnt10b showed little effects. It was also found that Wnt3a and Wnt5a expressions were significantly induced by LPS treatment. Consistently, knockdown of Wnt3a and Wnt5a blocked LPS-induced inflammatory responses, while treatment of recombinant Wnt3a and Wnt5a proteins rescued the inhibition of inflammatory responses by LGK974. Findings of this study showed that DKK-1 and LGK974 suppress LPS-induced inflammatory response by modulating Wnt/β-catenin pathway.
authors.affiliation: Department of Microbiology, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
authors.forename: Jaewoong
authors.initials: J
authors.lastname: Jang
authors.affiliation: Department of Microbiology, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
authors.forename: Yoonju
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Life Science, University of Seoul, Seoul, 130-743, Republic of Korea.
authors.forename: Youngeun
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Life Science, University of Seoul, Seoul, 130-743, Republic of Korea.
authors.forename: Eek-Hoon
authors.initials: EH
authors.lastname: Jho
authors.affiliation: Department of Microbiology, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
authors.forename: Yoosik
authors.initials: Y
authors.lastname: Yoon
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C501126:DKK1 protein, human; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011719:Pyrazines; D011725:Pyridines; D051153:Wnt Proteins; C586458:LGK974