Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver.
Acute endotoxemia is associated with production of acute phase proteins which regulate inflammatory responses to tissue injury. Consistent with DNA microarray experiments, we found that acute endotoxemia, induced by administration of lipopolysaccharide (LPS) to mice (1 mg/kg) or rats (5 mg/kg), resulted in increased expression of the hepatic acute phase protein, lipocalin 24p3, which was evident within 4 h and persisted for 24-48 h. Increases in 24p3 expression were also observed in the lung after LPS administration, as well as in isolated liver and lung macrophages, and Type II alveolar epithelial cells. The actions of LPS are dependent, in part, on Toll-like receptor (TLR) proteins. Macrophages from C3H/HeJ mice, which possess a nonfunctional TLR-4, expressed low levels of 24p3 mRNA when compared to cells from control C3H/OuJ mice. Whereas LPS administration increased 24p3 expression in lung and liver macrophages from control C3H/OuJ mice, minimal effects were observed in TLR-4 mutant mice demonstrating that TLR-4 is important in regulating 24p3 expression during acute endotoxemia. Promoters for genes encoding lipocalin proteins including 24p3 contain consensus sequences for transcription factors including NF-kappaB, and C/EBP. Acute endotoxemia resulted in NF-kappaB nuclear binding activity in both alveolar macrophages and Type II cells. In contrast, C/EBP activation was evident only in Type II cells, suggesting differential effects of LPS on these cell types. These data suggest that the acute phase response to acute endotoxemia involves induction of 24p3 in both the lung and liver. This protein may be important in restoring tissue homeostasis following LPS-induced injury.
Sunil
Vasanthi R
VR
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA. sunilvr@eohsi.rutgers.edu
Patel
Kinal J
KJ
Nilsen-Hamilton
Marit
M
Heck
Diane E
DE
Laskin
Jeffrey D
JD
Laskin
Debra L
DL
D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D019446:Endotoxemia / Q000235:genetics / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000473:pathology* / Q000503:physiopathology; D016676:Macrophages, Alveolar / Q000473:pathology / Q000502:physiology; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse