Effects of cytokines tumor necrosis factor alpha and interleukin 1 beta on endotoxin-mediated inhibition of endothelium-derived relaxing factor bioactivity and nitric oxide production in vascular endothelium.
Endotoxemia results in the release of cytokines that exert complex effects on the cardiovascular system. The purpose of this study was to 1) determine if interleukin 1 beta (IL1 beta) and tumor necrosis factor alpha (TNF alpha) elicit the release of endothelium-derived relaxing factor (EDRF) and nitric oxide derived from the constitutive nitric oxide synthase present in vascular endothelium, and 2) determine if these cytokines alter endotoxin-mediated decreases in EDRF bioactivity and nitric oxide production. Cultured bovine aortic endothelial cells were directly exposed to endotoxin, human recombinant TNF alpha, interleukin 1 beta, or a combination of endotoxin and cytokine for 1 h, followed by a second hour without endotoxin. Subsequently, both basal as well as agonist-stimulated (bradykinin) EDRF bioactivity and nitric oxide (NO) content of the effluent were quantitated. In additional experiments, endothelial cells were exposed acutely over a 30-min assay period to either endotoxin alone, cytokine alone, or endotoxin and cytokine. Following the 2-h incubation, endotoxin alone markedly reduced basal EDRF bioactivity and NO production (44 +/- 13% control, 66 +/- 13% control, respectively) and decreased bradykinin-stimulated EDRF bioactivity and NO production (58 +/- 5% control, 55 +/- 4% control, respectively). TNF alpha and IL1 beta did not stimulate EDRF release or NO production either acutely or after prolonged exposure, nor did they alter agonist-stimulated EDRF bioactivity and NO production. Similarly co-incubation of endotoxin with TNF alpha or IL1 beta failed to significantly alter the inhibitory effects of endotoxin on EDRF bioactivity and NO production.(ABSTRACT TRUNCATED AT 250 WORDS)
Myers
P R
PR
Department of Medicine, College of Medicine, Harry S. Truman Memorial Veterans Administration Hospital, Columbia, Missouri, USA.
Parker
J L
JL
Tanner
M A
MA
Adams
H R
HR
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D007022:Hypotension / Q000209:etiology / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000150:complications / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004731:Endotoxins; D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D001920:Bradykinin