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oxLDL antibody inhibits MCP-1 release in monocytes/macrophages by regulating Ca2+/K+ channel flow

Su, Jinyu; Zhou, Hui; Liu, Xianyan; Nilsson, Jan LU ; Fredrikson, Gunilla Nordin LU and Zhao, Ming LU (2017) In Journal of Cellular and Molecular Medicine 21(5). p.929-940
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... (More)

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+/Kir channel 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+/Kir channel 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
atherosclerosis, BI-204, Ca, FcgammarRIIB, inward rectifier K channel, MAPKs, MCP-1, oxLDL
in
Journal of Cellular and Molecular Medicine
volume
21
issue
5
pages
12 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:85007247536
ISSN
1582-1838
DOI
10.1111/jcmm.13033
language
English
LU publication?
yes
id
74d7c7d9-584e-43fe-82e0-717531f06ab0
date added to LUP
2017-04-21 13:41:42
date last changed
2017-04-22 03:00:02
@article{74d7c7d9-584e-43fe-82e0-717531f06ab0,
  abstract     = {<p>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<sup>+</sup>         <sub>ATP</sub>) 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 (K<sub>ir</sub>) and ensuing the opening of calcium channel. ERK MAPK inhibitor PD98059 inhibits oxLDL-induced Ca<sup>2+</sup>/K<sub>ir</sub> channel 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 Ca<sup>2+</sup>/K<sub>ir</sub> channel 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.</p>},
  author       = {Su, Jinyu and Zhou, Hui and Liu, Xianyan and Nilsson, Jan and Fredrikson, Gunilla Nordin and Zhao, Ming},
  issn         = {1582-1838},
  keyword      = {atherosclerosis,BI-204,Ca,FcgammarRIIB,inward rectifier K channel,MAPKs,MCP-1,oxLDL},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {929--940},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Cellular and Molecular Medicine},
  title        = {oxLDL antibody inhibits MCP-1 release in monocytes/macrophages by regulating Ca<sup>2+</sup>/K<sup>+</sup> channel flow},
  url          = {http://dx.doi.org/10.1111/jcmm.13033},
  volume       = {21},
  year         = {2017},
}