title: Mechanisms of human lymphotoxin beta receptor activation on upregulation of CCL5/RANTES production.
abstract: Human lymphotoxin-β receptor (LTβR), a member of the tumor necrosis factor receptor superfamily, plays an essential role in secondary lymphoid organ development, host defense, chemokine secretion, and apoptosis. In our study, LTβR activations by different stimulations were all found to induce RANTES secretion. Overexpression of LTβR or stimulation LTβR by ligands or agonistic antibody in human lung epithelial cells induced RANTES secretion However, the regulatory mechanism and the signaling cascade have not been fully elucidated. Therefore, the aim of this study was to elucidate the mechanism underlying LTβR-mediated RANTES production. Our study indicated that activation of JNK and ERK was important for the regulation of RANTES secretion. In addition, dominant negative mutants of ASK1, TAK1, and MEKK1 inhibited LTβR-induced RANTES expression. The dominant negative mutants of TRAF2, 3, and 5 also inhibited LTβR-mediated RANTES secretion. Chromatin immunoprecipitation analysis showed that LTβR activation induced the binding of c-Jun and NF-κB to the RANTES promoter. The results of this study show that LTβR activates ASK1, TAK1, and MEKK1 cascades via TRAF2, 3, and 5, resulting in the activation of JNK and ERK, which promotes the binding of c-Jun and NF-κB to the RANTES promoter, thereby increasing RANTES expression and secretion.
authors.affiliation: Department of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Division of Chest Medicine, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital.
authors.forename: Diana Yu-Wung
authors.initials: DY
authors.lastname: Yeh
authors.affiliation: Department of Urology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Chang
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Chin
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Lu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: mcchen@tmu.edu.tw.
authors.forename: Mei-Chieh
authors.initials: MC
authors.lastname: Chen
mesh_terms: D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053612:Janus Kinases / Q000187:drug effects; D053259:Lymphotoxin beta Receptor / Q000819:agonists* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics; D015854:Up-Regulation
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D053612:Janus Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: LTβR; MAPK; NF-κB; RANTES; TRAF; c-Jun