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

Autor: Gunilla Nordin Fredrikson, Xianyan Liu, Jinyu Su, Ming Zhao, Jan Nilsson, Hui Zhou
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
MAPK/ERK pathway
Potassium Channels
MAP Kinase Signaling System
p38 mitogen-activated protein kinases
chemistry.chemical_element
FcgammarRIIB
030204 cardiovascular system & hematology
Calcium
Models
Biological
Antibodies
Monocytes
03 medical and health sciences
Mice
0302 clinical medicine
MAPKs
Adenosine Triphosphate
Blocking antibody
Animals
Humans
Chemokine CCL2
inward rectifier K+ channel
oxLDL
Voltage-dependent calcium channel
Inward-rectifier potassium ion channel
Calcium channel
Macrophages
Receptors
IgG
Cell Biology
Original Articles
Potassium channel
Cell biology
Lipoproteins
LDL
Toll-Like Receptor 4
Ca2+
030104 developmental biology
RAW 264.7 Cells
Biochemistry
chemistry
Molecular Medicine
lipids (amino acids
peptides
and proteins)
Original Article
BI‐204
Calcium Channels
atherosclerosis
MCP‐1
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
1582-1838
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: