Hepatic expression of multiple acute phase proteins and down-regulation of nuclear receptors after acute endotoxin exposure.
Acute systemic lipopolysaccharide (endotoxin, LPS) exposure, which can lead to septic shock, enhances the hepatic expression of inflammatory and acute-phase proteins (APPs). To better understand how LPS aggravates damage, changes in hepatic gene expression after a single LPS dose was screened by using microarrays for 1176 rat genes. We detected more than 20 new potential LPS-induced APPs. Following acute LPS challenge, significant up-regulation of the steady-state mRNA levels of several important early transcription factors, such as c-jun and STAT3, and cytokine-associated genes, was observed. In contrast, RT-PCR analysis revealed marked down-regulation of the nuclear receptors RXRalpha, PXR, FXR, LXR, PPARalpha and CAR. Also genes encoding lipolytic, antioxidant as well as drug- and alcohol-metabolizing enzymes were down-regulated. These data suggest that acute LPS treatment induces important early transcription factors and co-ordinately down-regulates nuclear receptors, and that this results in altered expression of a large number of downstream genes.
Fang
Che
C
Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
Yoon
Seokjoo
S
Tindberg
Niclas
N
Järveläinen
Harri A
HA
Lindros
Kai O
KO
Ingelman-Sundberg
Magnus
M
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
D000209:Acute-Phase Proteins; D004731:Endotoxins; D018160:Receptors, Cytoplasmic and Nuclear