A network-based analysis of systemic inflammation in humans

• Published in: Nature (London) Vol. 437; no. 7061; pp. 1032 - 1037
• Main Authors: Calvano, Steve E., Xiao, Wenzhong, Richards, Daniel R., Felciano, Ramon M., Baker, Henry V., Cho, Raymond J., Chen, Richard O., Brownstein, Bernard H., Cobb, J. Perren, Tschoeke, S. Kevin, Miller-Graziano, Carol, Moldawer, Lyle L., Mindrinos, Michael N., Davis, Ronald W., Tompkins, Ronald G., Lowry, Stephen F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.10.2005; Nature Publishing; Nature Publishing Group
• Subjects: Acute Disease; Adolescent; Adult; Bioenergetics; Biological and medical sciences; Blood; Computational Biology; Deoxyribonucleic acid; Disease; DNA; Endotoxins; Endotoxins - blood; Endotoxins - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Profiling; Gene Expression Regulation - drug effects; Genomics; Humanities and Social Sciences; Humans; Immune system; Immunity, Innate - drug effects; Immunity, Innate - genetics; Immunity, Innate - immunology; Immunobiology; Immunological tolerance; Inflammation - blood; Inflammation - chemically induced; Inflammation - genetics; Inflammation - immunology; letter; Leukocytes; Leukocytes - drug effects; Leukocytes - immunology; Leukocytes - metabolism; Male; multidisciplinary; Oligonucleotide Array Sequence Analysis; RNA, Messenger - analysis; RNA, Messenger - genetics; Science; Science (multidisciplinary); Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Tumors; Human; Infection; Immune response; Leukocyte; Immune tolerance; Inflammation; Systemic; Gene expression
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature03985

Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens 1 , 2 , 3 , 4 , 5 . 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.