Role of membrane-anchored heparin-binding epidermal growth factor-like growth factor and CD9 on macrophages.
Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) is a potent mitogen for smooth-muscle cells (SMCs) belonging to the EGF family. We have previously determined that HB-EGF is expressed in macrophages and SMCs of human atherosclerotic lesions and that its membrane-anchored precursor, proHB-EGF, also has a juxtacrine mitogenic activity which is markedly enhanced by CD9, a surface marker of lymphohaemopoietic cells. Therefore, when both proHB-EGF and CD9 are expressed on macrophages, they may strongly promote the development of atherosclerosis. In the present study we have investigated the changes in proHB-EGF and CD9 in THP-1 cells during differentiation into macrophages and by the addition of oxidized low-density lipoproteins (OxLDL) and assessed juxtacrine growth activity of THP-1 macrophages for human aortic SMCs. HB-EGF and CD9 at both the mRNA and the protein level were up-regulated after differentiation into macrophages, and further expression of HB-EGF was induced by the addition of OxLDL or lysophosphatidylcholine. Juxtacrine induction by formalin-fixed growth was suppressed to control levels by an inhibitor of HB-EGF and was partially decreased by anti-CD9 antibodies. These results suggest that co-expression of proHB-EGF and CD9 on macrophages plays an important role in the development of atherosclerosis by a juxtacrine mechanism.
Ouchi
N
N
Second Department of Internal Medicine, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka, 565, Japan.
Kihara
S
S
Yamashita
S
S
Higashiyama
S
S
Nakagawa
T
T
Shimomura
I
I
Funahashi
T
T
Kameda-Takemura
K
K
Kawata
S
S
Taniguchi
N
N
Matsuzawa
Y
Y
D015703:Antigens, CD / Q000032:analysis / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D011498:Protein Precursors / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060245:Tetraspanin 29
D015703:Antigens, CD; C554869:CD9 protein, human; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D008562:Membrane Glycoproteins; D011498:Protein Precursors; D012333:RNA, Messenger; D060245:Tetraspanin 29; C099252:oxidized low density lipoprotein; D004815:Epidermal Growth Factor; D004247:DNA