title: Crosstalk between signals initiated from TLR4 and cell surface BAFF results in synergistic induction of proinflammatory mediators in THP-1 cells.
abstract: Cellular response to stimulation is mediated by meshwork of signaling pathways that may share common signaling adaptors. Here, we present data demonstrating that signaling pathways initiated from the membrane-bound form of B-cell activating factor (BAFF) can crosstalk with lipopolysaccharide (LPS)-induced signaling for synergistic expression of proinflammatory mediators in the human macrophage-like cell line THP-1. Co-treatment of the cells with BAFF-specific monoclonal antibody and LPS resulted in enhanced mitogen-activated protein kinase (MAPK)/mitogen- and stress-activated protein kinase (MSK)-mediated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 subunit (Ser276), which then interacts with CREB binding protein (CBP) for subsequent acetylation. Simultaneously, the phosphorylation of cyclic AMP-response element binding protein (CREB) was enhanced through the combined action of phosphatidylinositol-3-kinase (PI3K)/AKT and MAPK/MSK pathways, and the resulting phospho-CREB interacted with the NF-κB/CBP complex. Transfection of CREB-specific siRNA inhibited the BAFF-mediated enhancing effect indicating that the formation of the CREB/NF-κB/CBP complex is required for the synergistic induction of the proinflammatory genes. These findings indicate that BAFF-mediated reverse signaling can modulate LPS-induced inflammatory activation through regulation of NF-κB and CREB activity and point out the necessity to re-evaluate the role of BAFF in diseases where its expression is high in macrophages.
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea.
authors.forename: Su-Geun
authors.initials: SG
authors.lastname: Lim
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea.
authors.forename: Jae-Kwan
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Brain Science &Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea.
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea.
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D053264:B-Cell Activating Factor / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D046912:Multiprotein Complexes / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D000074084:THP-1 Cells; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D053264:B-Cell Activating Factor; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C498710:PAG1 protein, human; C495345:TLR4 protein, human; C505719:TNFSF13B protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D020929:Mitogen-Activated Protein Kinase Kinases