Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome.
BACKGROUND
Atherosclerosis is an inflammatory disease in which monocytes and macrophages have been suggested to play an essential role. The underlying signaling mechanisms are unknown thus far. We hypothesized that the human isoform of Toll-like receptor (hTLR)-4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis.


RESULTS
Expression of hTLR4 on circulating monocytes from 30 controls, 20 patients with stable angina (SA), 40 patients with unstable angina (UA), and 28 patients with acute myocardial infarction (AMI) was compared with the use of flow-cytometry and reverse transcription-polymerase chain reaction. Regulation of interleukin (IL)-12 and B7-1 as downstream events of TLR4 activation was analyzed after lipopolysaccharide stimulation of monocytes. TLR4-transfected Chinese hamster ovary (CHO) cells were used to identify potential hTLR4 ligands in the serum of patients with UA or AMI. Circulating hTLR4+/CD14+ monocytes were approximately 2.5-fold increased above controls and patients with SA in the UA and AMI groups (P<0.0001). This was paralleled by enhanced transcript levels of TLR4 and Myd88 in patients with UA and AMI (P<0.0001) and increased expression of IL-12 (UA 35.5+/-7.8, AMI 31.8+/-7.7 versus SA 2.2+/-0.5, controls 2.1+/-0.3 pg/mL; P<0.0002) and B7-1 (UA 27.3+/-14.4, AMI 22.6+/-11.1 versus SA 3.4+/-2.5, controls 2.4+/-2.3%; P<0.0001). Compared with serum from patients with UA and AMI, challenging TLR4-transfected CHO cells with serum from SA patients yielded only a weak response (P<0.0001). Coincubation with anti-heat shock protein 60 inhibited CHO cell activation.


CONCLUSIONS
UA and AMI are associated with enhanced expression and signaling events downstream of hTLR4 in circulating monocytes. These observations suggest hTLR4 activation as a signaling mechanism in immune-mediated progression of atherosclerosis.
Methe
Heiko
H
Department of Cardiology, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany. hmethe@mit.edu
Kim
Jong-Oh
JO
Kofler
Sieglinde
S
Weis
Michael
M
Nabauer
Michael
M
Koglin
Joerg
J
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000787:Angina Pectoris / Q000097:blood; D000943:Antigens, Differentiation / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D006331:Heart Diseases / Q000097:blood*; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000737:chemistry / Q000166:cytology*; D053594:Myeloid Differentiation Factor 88; D009203:Myocardial Infarction / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D008024:Ligands; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4