Treatment with granulocyte-macrophage colony-stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock

Scand J Infect Dis. 2010 Mar;42(3):164-71. doi: 10.3109/00365540903405768.


The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 +/- 21.0 vs 21.6 +/-9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy (p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin (p< 0.0001, r = 0.56) and mHLA-DR levels (p = 0.005, r = -0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Calcitonin / blood
  • Calcitonin Gene-Related Peptide
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use*
  • HLA-DR Antigens / biosynthesis
  • Humans
  • Immunologic Factors / therapeutic use*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Kynurenic Acid / blood
  • Kynurenine / blood*
  • Male
  • Middle Aged
  • Placebos / administration & dosage
  • Protein Precursors / blood
  • Quinolinic Acid / blood
  • Sepsis / drug therapy*
  • Serotonin / blood
  • Shock, Septic / drug therapy*
  • Treatment Outcome
  • Tryptophan / blood


  • CALCA protein, human
  • HLA-DR Antigens
  • Immunologic Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Placebos
  • Protein Precursors
  • Serotonin
  • Kynurenine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Tryptophan
  • Calcitonin
  • Quinolinic Acid
  • Kynurenic Acid
  • Calcitonin Gene-Related Peptide