Endogenous leukemia inhibitory factor attenuates endotoxin response.
Leukemia inhibitory factor (LIF) is induced in inflammation and likely plays a regulatory role. Using LIF-deficient mice (LIF-/-), we report here that endogenous LIF has a protective role in endotoxic shock and host defence. LIF-/- mice have heightened sensitivity to LPS in a LPS/D-galactosamine (D-Gal) sensitization model compared to wild-type mice (LIF+/+), enhanced thrombocytopenia and leukopenia, with increased hepatic necrosis, neutrophil sequestration in the lung and accelerated mortality. These findings correlated with 10-fold higher tumour necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6) serum levels and reduced IL-10 production in LIF-/- mice in response to LPS. Therefore, endogenous LIF attenuates the endotoxic shock response, enhances the expression of basal acute phase proteins and IL-10 production, which downregulates TNFalpha synthesis and release and thereby confers partial protection to endotoxemia.
Weber
Marietta A
MA
Cancer and Developmental Biology Laboratory, NCI-FCRDC, Frederick, MD, USA.
Schnyder-Candrian
Silvia
S
Schnyder
Bruno
B
Quesniaux
Valerie
V
Poli
Valeria
V
Stewart
Colin L
CL
Ryffel
Bernhard
B
D000210:Acute-Phase Reaction / Q000209:etiology; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D019446:Endotoxemia / Q000517:prevention & control*; D004731:Endotoxins / Q000097:blood*; D005688:Galactosamine / Q000008:administration & dosage / Q000494:pharmacology; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D053605:Leukemia Inhibitory Factor; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D000685:Serum Amyloid A Protein / Q000032:analysis; D012772:Shock, Septic / Q000517:prevention & control*; D013154:Spleen / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors
D004731:Endotoxins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005688:Galactosamine