G-CSF - AN ANTIINFLAMMATORY CYTOKINE

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 mu g 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-gamma 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.