Platelet-activating factor induces the processing of nuclear factor-kappaB p105 into p50, which mediates acute bowel injury in mice.
Platelet-activating factor (PAF), an endogenous proinflammatory phospholipid, when injected intravascularly to rats and mice, causes shock, acute bowel injury, and a rapid activation of NF-kappaB p50-p50 with upregulation of the chemokine CXCL2 in the intestine. In this study, we investigate the mechanism of NF-kappaB activation and the role of the NF-kappaB p50 subunit in PAF-induced shock and acute bowel injury. NF-kappaB p50-deficient mice and wild-type mice were anesthetized and tracheotomized, and their carotid artery was cannulated for blood pressure monitoring, blood sampling, and PAF administration. For determination of bowel injury, shock, and survival, PAF (2.2 microg/kg, intra-arterially, i.a.) was injected. Two hours later, animals were euthanized, and their small intestines were removed for histological examination. For biochemical studies, PAF (1.5 microg/kg i.a.) was administered and the small intestine removed after 15-60 min. We found that PAF induced an increase in p105 processing within 30 min, but there were no changes in the levels of the NF-kappaB inhibitory proteins IkappaBalpha and beta. NF-kappaB p50-deficient mice were protected against PAF-induced mortality, shock, intestinal hypoperfusion, and injury compared with wild-type animals. We also found that p50-deficient mice had decreased gene expression of CXCL2 and TNF and a decrease in CXCL2 protein production compared with wild-type mice. Our study suggests that PAF increases the processing of NF-kappaB p105 into p50, with upregulation of proinflammatory cytokines, which leads to PAF-induced systemic inflammatory response and acute bowel injury.
Liu
Shirley X L
SX
Departments of Pediatrics (Neonatology), Children's Memorial Research Center, Northwestern UniversityFeinberg School of Medicine (Medical School), Chicago, Illinois 60614, USA.
Tian
Runlan
R
Baskind
Heather
H
Hsueh
Wei
W
De Plaen
Isabelle G
IG
D000818:Animals; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007082:Ileum / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010972:Platelet Activating Factor; D011499:Protein Processing, Post-Translational; D013152:Splanchnic Circulation; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D052002:NF-kappa B p50 Subunit; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D010972:Platelet Activating Factor; D048069:Tumor Necrosis Factors; D000072000:NF-KappaB Inhibitor alpha; C073701:Nfkb1 protein, mouse