title: Granulocyte colony-stimulating factor (G-CSF) reduces not only gram-negative but also gram-positive infection-associated proinflammatory cytokine release by interaction between Kupffer cells and leukocytes.
abstract: OBJECTIVE
  An important principle for the beneficial effects of granulocyte colony-stimulating factor (G-CSF), a central mediator in the endogenous host response, is the reduction of systemic cytokine levels in various gram-negative models of sepsis and septic shock. There is debate, however, on whether G-CSF is protective also in gram-positive sepsis and acts directly or indirectly on macrophages and hepatic Kupffer cells (KC).
  
  
  METHODS
  KC were harvested from either G-CSF-(200 microg/kg bw i.v.) or saline-pretreated Sprague-Dawley rats and stimulated in vitro for subsequent assessment of cytokine release over 24 h.
  
  
  RESULTS
  Pretreatment with G-CSF led to a significant (p<0.05) inhibition of lipopolysaccharide (LPS)-induced release of TNF-alpha (-81%), IL-6 (-82%) and IL-1 beta (-57%). Exposure of KC to heat-killed Staphylococcus aureus (S. aureus/SAC) caused a 2- to 3-fold higher TNF-alpha release, but similar IL-6 levels when compared with those after LPS stimulation. Still, G-CSF proved to significantly reduce the release of both TNF-alpha and IL-6 upon KC exposure with SAC for 24h. Interestingly, in neutropenic animals (100mg/kg cyclophosphamide), G-CSF was not capable to blunt the LPS-induced cytokine release, indicating that the action of G-CSF on KC is not direct in nature but targets cellular communication and function of neutrophils.
  
  
  CONCLUSIONS
  The present results demonstrate that pretreatment with G-CSF in vivo effectively prevents the overactivation of KC by both gram-negative and gram-positive bacterial substances, probably via modulation of neutrophil function. Thus, inhibition of proinflammatory cytokine response through G-CSF may represent a promising hepatoprotective approach during systemic inflammation.
authors.affiliation: Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: C J
authors.initials: CJ
authors.lastname: Busch
authors.forename: G A
authors.initials: GA
authors.lastname: Wanner
authors.forename: M D
authors.initials: MD
authors.lastname: Menger
authors.forename: B
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016905:Gram-Negative Bacterial Infections / Q000276:immunology; D016908:Gram-Positive Bacterial Infections / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides; D008297:Male; D009503:Neutropenia / Q000139:chemically induced / Q000276:immunology; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor