title: Brief hypoxic stress downregulates E. coli-induced IL-1 alpha and IL-1 beta gene expression in perfused liver.
abstract: Hepatic cytokine gene expression is independently stimulated by circulating microbial products and reductions in the cellular O2 supply. Although these stimuli occur sequentially after gram-negative bacteremia, it is unknown whether their interplay augments production of interleukin (IL)-1 by the liver. We studied the effects of intraportal Escherichia coli (EC) bacteremia and secondary constant-flow hypoxia (Po2, approximately 46 Torr for 30 min) on IL-1 alpha and IL-1 beta gene expression in ex situ buffer-perfused rat livers over 180 min (n = 67). At t = 0, normoxic EC and normal saline (NS) controls received 10(9) live EC serotype 055:B5 and 0.9% NaCl, respectively; in livers subjected to EC+hypoxia-reoxygenation (H/R) and NS+H/R, hypoxia began 0.5 h after EC or NS and was followed by 120 min of reoxygenation. Portal and hepatic venous perfusates were serially analyzed for bacterial colony-forming units, O2 uptake, and aspartate aminotransferase. At 60 min (peak hypoxia) and 180 min, cDNAs for IL-1 alpha and IL-1 beta were hybridized to whole liver RNA, and IL-1 beta protein levels in venous perfusates were assessed. Intrahepatic levels of reduced glutathione (GSH) were measured as an index of oxidative stress. Compared with normoxic EC, IL-1 alpha transcripts decreased at 180 min in EC+H/R livers (P < 0.0001) as did IL-1 beta mRNA (P < 0.05), despite similar EC clearance, GSH levels, posthypoxic O2 uptake, and aspartate aminotransferase release. Hepatic secretion of IL-1 beta likewise fell in EC+H/R vs. EC controls (P < 0.005). Prostaglandin H synthase-2 (COX-2) message accumulation was not enhanced by H/R, and indomethacin did not reverse H/R-mediated suppression of IL-1 production. In contrast, H/R-related falls in EC-induced IL-1S expression were reversed by allopurinol or catalase. Thus brief hypoxic stress of the liver causing neither GSH depletion nor functional impairment downregulates postbacteremic IL-1 expression by a mechanism involving O2 radicals but not cyclooxygenase metabolites.
authors.affiliation: Department of Internal Medicine, Saint Louis University Health Sciences Center 63110, USA. Matuscgm@Wpogate.slu.edu
authors.forename: G M
authors.initials: GM
authors.lastname: Matuschak
authors.forename: C A
authors.initials: CA
authors.lastname: Johanns
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Gaynor
authors.forename: A J
authors.initials: AJ
authors.lastname: Lechner
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004927:Escherichia coli Infections / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D010100:Oxygen / Q000502:physiology; D010477:Perfusion; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D007375:Interleukin-1; D017382:Reactive Oxygen Species; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione; D010100:Oxygen