Effects of granulocyte colony-stimulating factor on plasma cytokine and cytokine receptor levels and on the in vivo host response to endotoxin in healthy men

Abstract

We investigated the effects of granulocyte colony-stimulating factor (G- CSF) on cytokine and cytokine receptor plasma levels and on the in vivo host response to Salmonella abortus equi endotoxin in healthy males. Twenty volunteers received 0.8 ng/kg endotoxin and saline intravenously 1 week apart in randomized order. Twelve hours before both experiments, 10 of these subjects were pretreated with 300 micrograms G-CSF subcutaneously. G-CSF itself increased granulocyte and monocyte counts and the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R) p55, and p75 and interleukin-1 receptor antagonist (IL-1ra). G-CSF did not influence plasma IL-1 beta and IL-6 levels. In the G-CSF-pretreated subjects endotoxin-induced surges in rectal temperature and in the plasma levels of TNF-alpha plasma levels were about 50% increased, and surges in the plasma levels of both sTNF- Rs and IL-1ra were about twice as high as in the control group. Endotoxin-induced increases in IL-6, cortisol, and heart rate were not modified by G-CSF pretreatment. Endotoxin administration induced a transient 50% reduction in leukocyte counts in the G-CSF-pretreated subjects that was not seen in the control group. We conclude that a single stand dose of G-CSF increases the plasma levels of cytokines and cytokine receptors and considerably modifies the host response of healthy humans to a low dose of endotoxin.

Treatment with granulocyte colony‐stimulating factor increases interleukin‐1 receptor antagonist levels during engraftment following allogeneic stem‐cell transplantation

“…Formally, this was shown for induction of IL-1ra by GM-CSF in neutrophils [44]. This and other studies [19][20][21][22] indicate that G-CSF has similar properties in vivo. In fact, several studies have recently addressed the feasibility and efficacy of G-CSF treatment for acute infectious diseases including sepsis in the nonneutropenic host (reviewed in [58]).…”

“…Besides promoting neutrophil maturation and differentiation there is ample evidence that G-CSF alters the immunophenotype of neutrophils [12][13][14][15][16] and monocytes [17], affects serum levels of selectins [18], interleukin (IL)-6, IL-8, IL-10, and tumour necrosis factor-α (TNF-α ) [19][20][21], as well as soluble p55 and p75 TNF receptors [19][20][21]. Among well-characterized factors known to be induced by G-CSF [19][20][21][22] the cytokine interleukin-1 receptor antagonist (IL-1ra) has attracted considerable attention for its role in host defense and haematopoiesis [23][24][25]. Owing to its potent anti-inflammatory properties, IL-1ra has been investigated as experimental treatment for various infectious and inflammatory conditions including gram-negative sepsis [26], rheumatoid arthritis [27], and graft-vs.-host disease (GVHD) [28].…”

Differential modulation of IL‐1‐induced endothelial adhesion molecules and transendothelial migration of granulocytes by G‐CSF

“…Another important effect of G-CSF is its anti-inflammatory role in the septic cascade in various pre-clinical (Görgen et al, 1992;Hartung et al, 1995;Lunblad et al, 1995) and clinical models (Lorenz et al, 1994). G-CSF promotes a cytokine response which may support the host defence (Hartung et al, 1995;Pollmächer et al, 1996). Since IL-1 plays a key role in bacterial infections (reviewed in Nelson, 1994), it is an important finding that G-CSF can counteract the granulocyte adhesion to endothelial cells induced by this inflammatory mediator.…”

Granulocyte colony‐stimulating factor (G‐CSF) downregulates its receptor (CD114) on neutrophils and induces gelatinase B release in humans

“…Finally, matrix metalloproteinases such as gelatinase B are known to cleave tumour necrosis factor (TNF) precursor to yield biologically active TNF (Gearing et al , 1994). This could, in part, explain why G‐CSF enhances TNF release in healthy volunteers or during human endotoxaemia (Pollmacher et al , 1996a,b).…”