Modulation of cytokine release and neutrophil function by granulocyte colony-stimulating factor during endotoxemia in humans.
In this double-blind, cross-over, placebo-controlled, randomized study, two groups of eight healthy male volunteers were challenged with endotoxin (4 ng/kg) on two occasions, once in conjunction with placebo and once with granulocyte colony-stimulating factor (G-CSF; 5 microg/kg). In group 1, G-CSF was administered intravenously 2 hours before endotoxin challenge; in group 2, G-CSF was administered subcutaneously 24 hours before endotoxin challenge. In group 1, G-CSF significantly enhanced the release of tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-8, IL-1 receptor antagonist (IL-1ra), and soluble TNF receptors. In group 2, G-CSF significantly reduced IL-8 concentrations and modestly attenuated TNF and IL-6 levels. In this group, IL-1ra and soluble TNF receptors were enhanced by G-CSF pretreatment and lipopolysaccharide (LPS)-induced soluble TNF receptor release was further augmented, whereas LPS-induced IL-1ra concentrations remained unaltered. Both pretreatments with G-CSF increased LPS-induced peripheral neutrophilia; the expression of CD11b, CD18, and CD67; and the release of elastase and lactoferrin. Both pretreatments also down-regulated neutrophil L-selectin expression and prevented the endotoxin-induced pulmonary neutrophil accumulation during the first 2 hours after endotoxin challenge. These data indicate that two different pretreatments with G-CSF result in differential effects on LPS-induced cytokine release but similar effects on LPS-induced neutrophil activation and changes in expression of cell surface molecules. Finally, regardless of the effects of G-CSF on LPS-induced cytokine release, G-CSF blocks LPS-induced pulmonary granulocyte accumulation.
Pajkrt
D
D
Department of Nuclear Medicine, and Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Center, University of Amsterdam, The Netherlands.
Manten
A
A
van der Poll
T
T
Tiel-van Buul
M M
MM
Jansen
J
J
Wouter ten Cate
J
J
van Deventer
S J
SJ
D015550:Cell Degranulation; D018592:Cross-Over Studies; D016207:Cytokines / Q000378:metabolism*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D006098:Granulocytes / Q000502:physiology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D012795:Sialoglycoproteins / Q000378:metabolism
D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D012795:Sialoglycoproteins; D016179:Granulocyte Colony-Stimulating Factor