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G-CSF - an anti-inflammatory cytokine

Department of Biochemical Pharmacology, University of Konstanz, Department of Clinical Immunology, Charité Berlin, Germany

H-D. Volk

Department of Biochemical Pharmacology, University of Konstanz, Department of Clinical Immunology, Charité Berlin, Germany

A. Wendel

Department of Biochemical Pharmacology, University of Konstanz, Department of Clinical Immunology, Charité Berlin, Germany

We have previously reported that in various macrophage populations prepared from G-CSF treated rats LPS-inducible TNF release was suppressed. In vitro, LPS induced liver cell death only when hepatocytes were cocultured with liver macrophages. Rat Kupffer cells from G-CSF treated donor animals were less potent in mediating LPS-inducible hepatocytotoxicity in vitro than cells from control animals. These ex vivo findings were confirmed in vivo by demonstrating that G-CSF treatment attenuated LPS-inducible circulating TNF levels and protected from liver injury and mortality.

We extended these observations to humans in two studies with G-CSF treated volunteers. In a pilot study, 11 subjects were treated single-blindly with 480 µg G-CSF s.c. (n = 7) or saline placebo (n = 4). Blood was taken at different time-points relative to G-CSF injection and cytokine release capacity was assessed in LPS stimulated whole blood incubations. In blood from G-CSF treated volunteers, we found reduced LPS-inducible TNF formation while the release of both soluble TNF receptor (sTNF-R) and interleukin 1 receptor antagonist (IL-1ra) were increased. In a second double-blind, randomized and controlled study, three groups of seven volunteers were treated once or twice 24 h apart with G-CSF or solvent placebo. Besides LPS, various stimuli were included to initiate cytokine release in a whole blood assay. The reduction of TNF formation (mean 53 % at 24 h after G-CSF) was different with the various stimuli. All stimuli increased IL-1ra (mean 14-fold) and sTNF-R (mean 3-fold) at 24 h after G-CSF. LPS-inducible IFN- and GM-CSF were significantly reduced. Our data indicate that the pattern of cytokines produced by human whole blood taken after G-CSF treatment in response to a variety of stimuli is shifted from pro- to anti-inflammatory mediators. These findings extend the knowledge on the pharmacology of G-CSF in animal models of the systemic inflammatory response syndrome and prompt a trial of G-CSF prophylaxis with this indication.

Journal of Endotoxin Research, Vol. 2, No. 3, 195-201 (1995)
DOI: 10.1177/096805199500200308


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