Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock.

BACKGROUND Severe sepsis results in a sustained deleterious immune dysregulation. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism, plays a pivotal role in immune tolerance and is induced during various inflammatory conditions. METHODS Plasma samples obtained from patients with septic shock (n = 38), severe sepsis (n = 35), or sepsis (n = 10) and from healthy donors (n = 26) were analyzed for IDO activity by high-performance liquid chromatography. Lymphocyte, monocyte, and regulatory T cell counts as well as monocytic human leukocyte antigen DR (HLA-DR) expression were quantified by flow cytometry. Peripheral blood mononuclear cells and purified CD14(+) and CD14(-) fractions were assayed in vitro for spontaneous and inducible IDO expression and activity. RESULTS IDO activity gradually increased according to sepsis severity, and septic patients who died had higher IDO activity on admission than did survivors (P = .013). Monocytes were a major source of active IDO in normal peripheral blood. The percentage and absolute number of circulating CD14(+) cells were increased in septic patients, and their monocytes remained fully able to produce functional IDO after NF-kappaB-independent interferon gamma stimulation but not through NF-kappaB-dependent Toll-like receptor engagement. CONCLUSIONS IDO activity is increased during severe sepsis and septic shock and is associated with mortality. IDO production could be used to better characterize monocyte reprogramming in sepsis.

[1]  K. Iwabuchi,et al.  Co‐operative action of interleukin‐10 and interferon‐γ to regulate dendritic cell functions , 2009, Immunology.

[2]  F. Geissmann,et al.  Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T‐cell responses , 2008, Immunology and cell biology.

[3]  J. Cavaillon,et al.  NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance. , 2000, American journal of respiratory and critical care medicine.

[4]  P. Tak,et al.  Noncanonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation , 2007 .

[5]  J. Laine,et al.  HIGH ACTIVITY OF INDOLEAMINE 2,3 DIOXYGENASE ENZYME PREDICTS DISEASE SEVERITY AND CASE FATALITY IN BACTEREMIC PATIENTS , 2010, Shock.

[6]  J. Bienvenu,et al.  The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. , 2004, Immunology letters.

[7]  Shizuo Akira,et al.  Signaling to NF-kappaB by Toll-like receptors. , 2007, Trends in molecular medicine.

[8]  P. Tak,et al.  Non-canonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation , 2007 .

[9]  B. Drénou,et al.  Early Circulating Lymphocyte Apoptosis in Human Septic Shock Is Associated with Poor Outcome , 2002, Shock.

[10]  J. Pugin,et al.  Is the measurement of monocytes HLA-DR expression useful in patients with sepsis? , 2006, Intensive Care Medicine.

[11]  Shizuo Akira,et al.  Signaling to NF-?B by Toll-like receptors , 2007 .

[12]  T. Hohl,et al.  Selective Expansion of the Monocytic Lineage Directed by Bacterial Infection1 , 2009, The Journal of Immunology.

[13]  T. Šarić,et al.  CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. , 2006, Blood.

[14]  C. Meisel,et al.  Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. , 2005, Clinical chemistry.

[15]  M. Albert,et al.  A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. , 2005, Blood.

[16]  N. Voirin,et al.  Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock , 2006, Intensive Care Medicine.

[17]  W. Powell,et al.  Human CD4+CD25+ Regulatory T Lymphocytes Inhibit Lipopolysaccharide-Induced Monocyte Survival through a Fas/Fas Ligand-Dependent Mechanism1 , 2006, The Journal of Immunology.

[18]  Cory M. Robinson,et al.  NF-kappa B activation contributes to indoleamine dioxygenase transcriptional synergy induced by IFN-gamma and tumor necrosis factor-alpha. , 2006, Cytokine.

[19]  D. Fuchs,et al.  Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation. , 2005, Blood.

[20]  N. Sevenet,et al.  Gene profiling in human blood leucocytes during recovery from septic shock , 2008, Intensive Care Medicine.

[21]  M. Williams,et al.  Granulocyte-macrophage colony-stimulating factor induces activation and restores respiratory burst activity in monocytes from septic patients. , 1998, The Journal of infectious diseases.

[22]  Djillali Annane,et al.  Septic shock , 2005, The Lancet.

[23]  J. Cinatl,et al.  INCREASED PLASMA KYNURENINE VALUES AND KYNURENINE-TRYPTOPHAN RATIOS AFTER MAJOR TRAUMA ARE EARLY INDICATORS FOR THE DEVELOPMENT OF SEPSIS , 2008, Shock.

[24]  K. Asadullah,et al.  Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. , 1997, Nature medicine.

[25]  Jun Sik Lee,et al.  Blockade of Indoleamine 2,3-Dioxygenase Protects Mice against Lipopolysaccharide-Induced Endotoxin Shock1 , 2009, The Journal of Immunology.

[26]  J. Bienvenu,et al.  Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25− lymphocytes , 2004, Critical care medicine.

[27]  S. Lemeshow,et al.  A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. , 1993, JAMA.

[28]  L. Moldawer,et al.  MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis , 2007, The Journal of experimental medicine.

[29]  M. Williams,et al.  Monocyte anergy in septic shock is associated with a predilection to apoptosis and is reversed by granulocyte-macrophage colony-stimulating factor ex vivo. , 1998, The Journal of infectious diseases.

[30]  D. Munn,et al.  Ligation of B7-1/B7-2 by Human CD4+ T Cells Triggers Indoleamine 2,3-Dioxygenase Activity in Dendritic Cells1 , 2004, The Journal of Immunology.

[31]  S. Blecher,et al.  Expression of cell surface receptors and oxidative metabolism modulation in the clinical continuum of sepsis , 2008, Critical care.

[32]  D. Munn,et al.  Ido expression by dendritic cells: tolerance and tryptophan catabolism , 2004, Nature Reviews Immunology.

[33]  S. Akira,et al.  Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. , 2006, Immunity.

[34]  B. Drénou,et al.  Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. , 2004, American journal of respiratory and critical care medicine.

[35]  F. Venet,et al.  Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony , 2008, Molecular medicine.

[36]  M. Murray.  Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. , 2003, The Lancet. Infectious diseases.

[37]  D. Fuchs,et al.  ENHANCED ENZYMATIC DEGRADATION OF TRYPTOPHAN BY INDOLEAMINE 2,3-DIOXYGENASE CONTRIBUTES TO THE TRYPTOPHAN-DEFICIENT STATE SEEN AFTER MAJOR TRAUMA , 2005, Shock.

[38]  K. Tarte,et al.  Functional alteration of the lymphoma stromal cell niche by the cytokine context: role of indoleamine-2,3 dioxygenase. , 2009, Cancer research.

[39]  B. Drénou,et al.  Down-modulation of granulocyte macrophage-colony stimulating factor receptor on monocytes during human septic shock , 2006, Critical care medicine.

[40]  P. Krause,et al.  Prostaglandin E2 is a key factor for monocyte‐derived dendritic cell maturation: enhanced T cell stimulatory capacity despite IDO , 2007, Journal of leukocyte biology.

[41]  S Lemeshow,et al.  The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. , 1996, JAMA.

[42]  N. Voirin,et al.  Decreased Expression of the Fractalkine Receptor CX3CR1 on Circulating Monocytes as New Feature of Sepsis-Induced Immunosuppression , 2008, The Journal of Immunology.

[43]  B. Mougin,et al.  Systemic transcriptional analysis in survivor and non-survivor septic shock patients: a preliminary study. , 2006, Immunology letters.

[44]  R. Hotchkiss,et al.  The pathophysiology and treatment of sepsis. , 2003, The New England journal of medicine.

[45]  D. Fuchs,et al.  HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. , 2007, Blood.

[46]  C. Chung,et al.  Increased circulating regulatory T cells (CD4+CD25+CD127−) contribute to lymphocyte anergy in septic shock patients , 2009, Intensive Care Medicine.

[47]  Rudi Beyaert,et al.  Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients* , 2006, Critical care medicine.

[48]  P. Haslett,et al.  A whole blood assay to assess peripheral blood dendritic cell function in response to Toll-like receptor stimulation. , 2006, Journal of immunological methods.

[49]  B. Brüne,et al.  Activation-Induced Depletion of Protein Kinase Cα Provokes Desensitization of Monocytes/Macrophages in Sepsis1 , 2005, The Journal of Immunology.

[50]  Mitchell M. Levy,et al.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference , 2003, Intensive Care Medicine.

[51]  D. Richardson,et al.  Antioxidants Inhibit Indoleamine 2,3-Dioxygenase in IFN-γ-Activated Human Macrophages: Posttranslational Regulation by Pyrrolidine Dithiocarbamate1 , 2001, The Journal of Immunology.

[52]  Ignacio Anegon,et al.  IDO expands human CD4+CD25high regulatory T cells by promoting maturation of LPS‐treated dendritic cells , 2007, European journal of immunology.