An essential function for MKP5 in the formation of oxidized low density lipid-induced foam cells.
The uptake of oxidized low density lipoprotein (ox-LDL) by macrophages usually leads to the formation of lipid-laden macrophages known as "foam cells," and this process plays an important role in the development of atherosclerosis. Ox-LDL activates mitogen-activated protein kinase (MAP) kinases and nuclear factor (NF)-κB, and activations of p38 and NF-κB are important for the formation of foam cells. MAP kinase phosphatase (MKP) 5 is a member of the dual specificity phosphatases (DUSPs) family that can selectively dephosphorylate activated MAPKs to regulate innate and adaptive immune responses. However, the role of MKP5 in the formation of foam cells remains unknown. Here, we found that stimulation of ox-LDL induces the expression of MKP5 in macrophages. MKP5 deficiency blocked the uptake of ox-LDL and the formation of foam cells. Further analysis revealed that deletion of MKP5 reduced the ox-LDL-induced activation of NF-κB. Also, MKP5 deficiency markedly inhibited the production of TNF-α, but enhanced the levels of TGF-β1 in ox-LDL-stimulated macrophages. Moreover, inhibition of NF-κB by p65 RNAi significantly reduced foam cell formation in macrophages from WT mice relative to MKP5-deficient mice. Thus, MKP5 has an essential role in the formation of foam cells through activation of NF-κB, and MKP5 represents a novel target for the therapeutic intervention of atherosclerosis.
Department of Stomatology, Shanghai Jiading Central Hospital, China.
Li-Jun
LJ
Luo
Feng
F
Liu
Xing-Yu
XY
Wang
Tian-Yun
TY
Dai
Ya-Lei
YL
Dai
Chen
C
Dong
Bao-Xue
BX
Ge
D000818:Animals; D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D005260:Female; D005487:Foam Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D008077:Lipoproteins, LDL / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology*; D034622:RNA Interference; D051116:Receptors, Scavenger / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology
D008077:Lipoproteins, LDL; D016328:NF-kappa B; D051116:Receptors, Scavenger; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D019892:eIF-2 Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; C505617:Dusp10 protein, mouse; D054637:Dual-Specificity Phosphatases