Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4.
BACKGROUND
Coronary artery bypass grafting with the use of cardiopulmonary bypass is known to mediate an inflammatory response. The stress-inducible heat-shock protein (HSP) 70 has been detected in myocardial cells after CABG, and toll-like receptors (TLRs) are suggested as putative signaling receptors for the HSPs, mediating synthesis of inflammatory cytokines. The main aims of our study were to explore the release of HSP70 and the regulation of monocyte TLR-2 and TLR-4 expression after CABG.


RESULTS
Twenty patients referred for elective CABG were included in this study. Using immunoassays, we detected HSP70 in plasma after CABG, with peak concentration immediately after surgery. Interleukin-6 in plasma reached peak concentration 5 hours after surgery. Monocyte CD14, TLR-2, and TLR-4 expression, as analyzed by flow cytometry, was initially downregulated. On day 1, CD14 expression normalized, whereas TLR-2 and TLR-4 expression was upregulated. TLR-4 was significantly upregulated even on postoperative day 2. Additional experiments revealed that peritoneal macrophages from control (C3H/HeN) mice responded to HSP70 with release of tumor necrosis factor, whereas macrophages from mutated TLR-4 (C3H/HeJ) mice were unresponsive. In vitro, human adherent monocytes responded to recombinant HSP70 with interleukin-6 and tumor necrosis factor release. CD14 and TLR-4 monoclonal antibodies inhibited the cytokine response.


CONCLUSIONS
In this study, we observed an immediate release of HSP70 into the circulation and a modulation of monocyte TLR-2 and TLR-4 expression after CABG. TLR-4 and CD14 appear to be involved in an HSP70-mediated activation of innate immunity.
Dybdahl
Brit
B
Faculty of Medicine, Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway. brit.dybdahl@medisin.ntnu.no
Wahba
Alexander
A
Lien
Egil
E
Flo
Trude H
TH
Waage
Anders
A
Qureshi
Nilofer
N
Sellevold
Olav F M
OF
Espevik
Terje
T
Sundan
Anders
A
D000368:Aged; D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D001026:Coronary Artery Bypass / Q000009:adverse effects; D003324:Coronary Artery Disease / Q000601:surgery*; D029721:Drosophila Proteins; D005260:Female; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000209:etiology / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011184:Postoperative Period; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors