Cardiac myocytes activated by septic plasma promote neutrophil transendothelial migration: role of platelet-activating factor and the chemokines LIX and KC.
Cardiac myocytes isolated from rats with peritonitis (cecal ligation and perforation; CLP) promote PMN transendothelial migration. Herein, we assessed (1) the mechanisms involved in cardiac myocyte activation during peritonitis and (2) the means by which these activated myocytes promote PMN transendothelial migration. Plasma obtained from mice subjected to CLP (septic plasma) activated isolated cardiac myocytes as evidenced by (1) increased nuclear levels of nuclear factor-kappaB (NF-kappaB) and (2) their ability to promote PMN migration across endothelial cell monolayers. Pretreatment of septic plasma with an antibody against tumor necrosis factor-alpha (TNF-alpha), but not interleukin-1beta (IL-1beta), blunted the ability of septic plasma to activate the myocytes. However, septic plasma obtained from TNF-alpha-deficient mice could still activate the myocytes; an effect attenuated by an antibody against IL-1beta. If the myocytes were pretreated with a proteasome inhibitor (MG 132) to prevent NF-kappaB activation, the myocyte-induced PMN transendothelial migration was compromised. The activated myocytes released platelet-activating factor (PAF), and myocyte-induced PMN migration was abrogated by a PAF receptor antagonist (WEB 2086). These myocytes also released the CXC chemokines LIX and KC; an event prevented by MG 132. Antibodies against LIX and KC abrogated the myocyte-induced PMN migration. However, LIX and KC, but not PAF, could promote PMN migration when used at concentrations produced by activated myocytes. These observations indicate that TNF-alpha and IL-1beta are, in part, responsible for the ability of septic plasma to activate cardiac myocytes. The activated myocytes promote PMN transendothelial migration, an effect attributable to LIX and KC, and possibly, PAF.
Vascular Cell Biology Laboratory, Lawson Health Research Institute and the Department of Physiology, University of Western Ontario, London, Ontario, Canada.
W Sean
WS
Madorin
Tao
T
Rui
Naohito
N
Sugimoto
Osamu
O
Handa
Gediminas
G
Cepinskas
Peter R
PR
Kvietys
D000818:Animals; D000831:Animals, Newborn; D001381:Azepines / Q000494:pharmacology; D002432:Cecum; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000378:metabolism / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003546:Cysteine Endopeptidases; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D007416:Intestinal Perforation / Q000150:complications; D007976:Leupeptins / Q000494:pharmacology; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D010538:Peritonitis / Q000097:blood / Q000209:etiology; D010949:Plasma; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D018805:Sepsis / Q000097:blood* / Q000209:etiology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D001381:Azepines; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C094739:Cxcl5 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011480:Protease Inhibitors; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C052518:WEB 2086; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde