title: oxLDL antibody inhibits MCP-1 release in monocytes/macrophages by regulating Ca2+/K+channel flow.
abstract: oxLDL peptide vaccine and its antibody adoptive transferring have shown a significantly preventive or therapeutic effect in atherosclerotic animal model. The molecular mechanism behind this is obscure. Here, we report that oxLDL induces MCP-1 release in monocytes/macrophages through their TLR-4 (Toll-like receptor 4) and ERK MAPK pathway and is calcium/potassium channel-dependent. Using blocking antibodies against CD36, TLR-4, SR-AI and LOX-1, only TLR-4 antibody was found to have an inhibitory effect and ERK MAPK-specific inhibitor (PD98059) was found to have a dramatic inhibitory effect compared to inhibitors of other MAPK group members (p38 and JNK MAPKs) on oxLDL-induced MCP-1 release. The release of cytokines and chemokines needs influx of extracellular calcium and imbalance of efflux of potassium. Nifedipine, a voltage-dependent calcium channel (VDCC) inhibitor, and glyburide, an ATP-regulated potassium channel (K+ATP) inhibitor, inhibit oxLDL-induced MCP-1 release. Potassium efflux and influx counterbalance maintains the negative potential of macrophages to open calcium channels, and our results suggest that oxLDL actually induces the closing of potassium influx channel - inward rectifier channel (Kir) and ensuing the opening of calcium channel. ERK MAPK inhibitor PD98059 inhibits oxLDL-induced Ca2+/Kirchannel alterations. The interfering of oxLDL-induced MCP-1 release by its monoclonal antibody is through its FcγRIIB (CD32). Using blocking antibodies against FcγRI (CD64), FcγRIIB (CD32) and FcγRIII (CD16), only CD32 blocking antibody was found to reverse the inhibitory effect of oxLDL antibody on oxLDL-induced MCP-1 release. Interestingly, oxLDL antibody specifically inhibits oxLDL-induced ERK MAPK activation and ensuing Ca2+/Kirchannel alterations, and MCP-1 release. Thus, we found a molecular mechanism of oxLDL antibody on inhibition of oxLDL-induced ERK MAPK pathway and consequent MCP-1 release.
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China.
authors.forename: Xianyan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Clinical Sciences, Scania University Hospital, Malmö Lund University, Malmö, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Sciences, Scania University Hospital, Malmö Lund University, Malmö, Sweden.
authors.forename: Gunilla Nordin
authors.initials: GN
authors.lastname: Fredrikson
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000276:immunology*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D017452:Receptors, IgG / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000906:Antibodies; C111835:CCL2 protein, human; D015220:Calcium Channels; D018932:Chemokine CCL2; C080571:Fc gamma receptor IIB; D008077:Lipoproteins, LDL; D015221:Potassium Channels; D017452:Receptors, IgG; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: BI-204; Ca2+; FcgammarRIIB; MAPKs; MCP-1; atherosclerosis; inward rectifier K+ channel; oxLDL