Altered gene expression in acute systemic inflammation detected by complete coverage of the human liver transcriptome.
The goal of the current study was to provide complete coverage of the liver transcriptome with human probes corresponding to every gene expressed in embryonic, adult, and/or cancerous liver. We developed dedicated tools, namely, the Liverpool nylon array of complementary DNA (cDNA) probes for approximately 10,000 nonredundant genes and the LiverTools database. Inflammation-induced transcriptome changes were studied in liver tissue samples from patients with an acute systemic inflammation and from control subjects. One hundred and fifty-four messenger RNAs (mRNA) correlated statistically with the extent of inflammation. Of these, 134 mRNA samples were not associated previously with an acute-phase (AP) response. The hepatocyte origin and proinflammatory cytokine responsiveness of these mRNAs were confirmed by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) in cytokine-challenged hepatoma cells. The corresponding gene promoters were enriched in potential binding sites for inflammation-driven transcription factors in the liver. Some of the corresponding proteins may provide novel blood markers of clinical relevance. The mRNAs whose level is most correlated with the AP extent (P <.05) were enriched in intracellular signaling molecules, transcription factors, glycosylation enzymes, and up-regulated plasma proteins. In conclusion, the hepatocyte responded to the AP extent by fine tuning some mRNA levels, controlling most, if not all, intracellular events from early signaling to the final secretion of proteins involved in innate immunity. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Coulouarn
Cédric
C
INSERM Unité 519 and Faculté de Médecine-Pharmacie, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides, Rouen, France.
Lefebvre
Grégory
G
Derambure
Céline
C
Lequerre
Thierry
T
Scotte
Michel
M
Francois
Arnaud
A
Cellier
Dominique
D
Daveau
Maryvonne
M
Salier
Jean-Philippe
JP
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016207:Cytokines / Q000235:genetics; D030541:Databases, Genetic; D005260:Female; D015870:Gene Expression; D005819:Genetic Markers; D006505:Hepatitis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D022781:Hepatocytes / Q000276:immunology / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000235:genetics
D016207:Cytokines; D005819:Genetic Markers; D012333:RNA, Messenger