Altered oxygen tension modulates cytokine-induced signal transduction in polymorphonuclear leukocytes: regulation of the GPLD pathway

• Published in: Shock (Augusta, Ga.) Vol. 5; no. 2; p. 97
• Main Authors: Derevianko, A, Graeber, T, D'Amico, R, Simms, H H
• Format: Journal Article
• Language: English
• Published: United States 01-02-1996
• Subjects: Adenosine Triphosphate - metabolism; Cytokines - administration & dosage; GTP-Binding Proteins - drug effects; GTP-Binding Proteins - metabolism; Humans; Hypoxia - metabolism; Neutrophils - drug effects; Neutrophils - metabolism; Oxygen - physiology; Signal Transduction - physiology
• ISSN: 1073-2322
• DOI: 10.1097/00024382-199602000-00003

We investigated the effect of alterations in buffer oxygen tensions from normoxia (PO2 = 180-200 mm/Hg) to hypoxia (PO2 < 30 mm/HG) and then reoxygenation (PO2 > 140 mmHg) on the GPLD-pathway by measuring phosphatidylethanol formation in the presence of ethanol and subsequent NADPH oxidase activation and O2-production in polymorphonuclear leukocytes (PMN). Experiments were performed with PMN stimulated with either interleukin (IL)-8, tumor necrosis factor (TNF)-alpha, or IL-1 beta in the presence or absence of fibronectin. Hypoxia exerted a downregulating effect on this pathway and reoxygenation restored GPLD activation to levels seen during normoxia; however, supraphysiological concentrations of cytokines were able to reverse this pattern. Changes in GPLD activation correlated best with changes in O2-production during the hypoxia to hypoxia/reoxygenation transition induced by TNF-alpha-Fn and IL-1 beta +/- Fn. Thus, changes in oxygen tension can directly modulate the extent of the PMN response to stimulation by IL-8, TNF-alpha, or IL-1 beta, and activation of the GPLD-pathway appears to be highly sensitive to hypoxia and hypoxia/reoxygenation.