A network-based analysis of systemic inflammation in humans

Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.

[1]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[2]  S. Orkin,et al.  The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex , 1987, Nature.

[3]  A C Allison,et al.  The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. , 1990, The Journal of clinical investigation.

[4]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. , 1992, Chest.

[5]  F. Buttgereit,et al.  A hierarchy of ATP-consuming processes in mammalian cells. , 1995, The Biochemical journal.

[6]  R. W. Davis,et al.  Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[8]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H. Volk,et al.  Impaired antigen presentation by human monocytes during endotoxin tolerance. , 2000, Blood.

[10]  N. Sampas,et al.  Molecular classification of cutaneous malignant melanoma by gene expression profiling , 2000, Nature.

[11]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[12]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[13]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[14]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Fink.  Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. , 2001, Critical care clinics.

[16]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  John Land,et al.  Association between mitochondrial dysfunction and severity and outcome of septic shock , 2002, The Lancet.

[18]  Y. Guan,et al.  Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? , 2002, The Lancet.

[19]  E. Crouser,et al.  Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity , 2002, Critical care medicine.

[20]  H. Volk,et al.  Multiple Mechanisms of Reduced Major Histocompatibility Complex Class II Expression in Endotoxin Tolerance* , 2003, The Journal of Biological Chemistry.

[21]  S. Calvano,et al.  Effects of Drotrecogin Alfa (Activated) in Human Endotoxemia , 2004, Shock.

[22]  Tetsuya Watanabe,et al.  Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death , 2005, Nature.

[23]  L. Astrakas,et al.  Burn injury causes mitochondrial dysfunction in skeletal muscle. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Jeffrey Robbins,et al.  Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death , 2005, Nature.