Interleukin-6 enhances matrix metalloproteinase-14 expression via the RAF-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2-activator protein-1 pathway.
1. Interleukin (IL)-6 is a pivotal cytokine that regulates extracellular matrix (ECM) metabolism by increasing collagen degradation via activation of matrix metalloproteinases (MMPs), such as MMP-14. In the present study, we investigated the role of IL-6 in atherosclerotic plaque and signalling pathways in apolipoprotein E-deficient (ApoE(-/-)) mice. 2. Twenty-five male ApoE(-/-) mice were fed a high-fat diet and atherosclerotic lesions in the right common carotid artery were induced by perivascular placement of a constrictive collar. Immunohistochemical analysis detected expression of IL-6 and MMP-14 in atherosclerotic lesions of the right common carotid artery. 3. On silencing activator protein (AP)-1 expression with a specific small interfering RNA, 75% of the IL-6-induced increase in MMP-14 expression was abolished through the RAF-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2-AP-1 pathway. 4. These findings suggest a novel molecular pathway for inflammation-associated ECM dysregulation, which may account for atherosclerotic plaque rupture.
Feng
Min
M
Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University Qilu Hospital, Jinan, Shandong, China.
Cai
Xiao-Jun
XJ
Zhang
Wei
W
Liu
Xiao-Ling
XL
Chen
Liang
L
Zhang
Yun
Y
Zhang
Ming-Xiang
MX
Zhang
Mei
M
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002340:Carotid Artery Diseases / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism
D001057:Apolipoproteins E; D004041:Dietary Fats; D015850:Interleukin-6; D018808:Transcription Factor AP-1; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D053511:Matrix Metalloproteinase 14