Role of STK in mouse liver macrophage and endothelial cell responsiveness during acute endotoxemia.
Acute endotoxemia is associated with excessive production of proinflammatory mediators by hepatic macrophages and endothelial cells, which have been implicated in liver injury and sepsis. In these studies, we analyzed the role of MSP and its receptor STK in regulating the activity of these cells. Acute endotoxemia, induced by administration of LPS (3 mg/kg) to mice, resulted in increased expression of STK mRNA and protein in liver macrophages and endothelial cells, an effect that was dependent on TLR-4. This was correlated with decreased MSP and increased pro-MSP in serum. In Kupffer cells, but not endothelial cells, MSP suppressed LPS-induced NOS-2 expression, with no effect on COX-2. LPS treatment of mice caused a rapid (within 3 h) increase in the proinflammatory proteins NOS-2, IL-1beta, and TNF-alpha, as well as TREM-1 and TREM-3 and the anti-inflammatory cytokine IL-10 in liver macrophages and endothelial cells. Whereas LPS-induced expression of proinflammatory proteins was unchanged in STK-/- mice, IL-10 expression was reduced significantly. Enzymes mediating eicosanoid biosynthesis including COX-2 and mPGES-1 also increased in macrophages and endothelial cells after LPS administration. In STK-/- mice treated with LPS, mPGES-1 expression increased, although COX-2 expression was reduced. LPS-induced up-regulation of SOD was also reduced in STK-/- mice in liver macrophages and endothelial cells. These data suggest that MSP/STK signaling plays a role in up-regulating macrophage and endothelial cell anti-inflammatory activity during hepatic inflammatory responses. This may be important in protecting the liver from tissue injury.
Laskin
Debra L
DL
Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, 160 Frelinghuysen Rd., Piscataway, NJ 08854, USA. laskin@eohsi.rutgers.edu
Chen
Li
L
Hankey
Pamela A
PA
Laskin
Jeffrey D
JD
D000208:Acute Disease; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000276:immunology / Q000473:pathology*; D008107:Liver Diseases / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000187:drug effects; D012697:Serine Endopeptidases / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000502:physiology*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D012697:Serine Endopeptidases; C108816:myelencephalon-specific serine protease
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