title: 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.
abstract: 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.
authors: Department of Nephrology and Intensive Care Medicine, Charité University Medicine, Campus Virchow, Berlin, Germany. schefold@charite.de
authors: Joerg C
authors: JC
authors: Schefold
authors: Jan-Philip
authors: JP
authors: Zeden
authors: Rene
authors: R
authors: Pschowski
authors: Ben
authors: B
authors: Hammoud
authors: Christina
authors: C
authors: Fotopoulou
authors: Dietrich
authors: D
authors: Hasper
authors: Gerhard
authors: G
authors: Fusch
authors: Stephan
authors: S
authors: Von Haehling
authors: Hans-Dieter
authors: HD
authors: Volk
authors: Christian
authors: C
authors: Meisel
authors: Christine
authors: C
authors: Schütt
authors: Petra
authors: P
authors: Reinke
mesh_terms: D000368:Aged; D002116:Calcitonin / Q000097:blood; D015740:Calcitonin Gene-Related Peptide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011498:Protein Precursors / Q000097:blood; D017378:Quinolinic Acid / Q000097:blood; D018805:Sepsis / Q000188:drug therapy*; D012701:Serotonin / Q000097:blood; D012772:Shock, Septic / Q000188:drug therapy*; D016896:Treatment Outcome; D014364:Tryptophan / Q000097:blood
chemical_list: C000606589:CALCA protein, human; D006684:HLA-DR Antigens; D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010919:Placebos; D011498:Protein Precursors; D012701:Serotonin; D007737:Kynurenine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D014364:Tryptophan; D002116:Calcitonin; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D015740:Calcitonin Gene-Related Peptide