Altered oxygen tension modulates cytokine-induced signal transduction in polymorphonuclear leukocytes: regulation of the GPLD pathway.
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.
Derevianko
A
A
Brown University School of Medicine, Department of Surgery, Rhode Island Hospital, Providence 02903, USA.
Graeber
T
T
D'Amico
R
R
Simms
H H
HH
D000255:Adenosine Triphosphate / Q000378:metabolism; D016207:Cytokines / Q000008:administration & dosage*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D000255:Adenosine Triphosphate; D019204:GTP-Binding Proteins; D010100:Oxygen