Increased tolerance to endotoxin by granulocyte-macrophage colony-stimulating factor-deficient mice.
The contribution of granulocyte-macrophage CSF (GM-CSF) to endotoxin-mediated septic shock has been assessed by treating GM-CSF-deficient mice with LPS. Hypothermia and loss in body weight were markedly attenuated in LPS-treated GM-CSF-deficient mice compared with similarly treated control mice; moreover, the levels of circulating IFN-gamma, IL-1alpha, and IL-6 were lower in LPS-treated GM-CSF-deficient mice than LPS-treated control mice. Intriguingly, the peak levels of TNF-alpha in response to LPS treatment were the same in the serum of GM-CSF-deficient mice and control mice, although in GM-CSF-deficient mice, TNF-alpha persisted longer. Activation of macrophages by LPS, resulting in expression of cytokines including TNF-alpha and IL-1, is thought to underlie endotoxin-mediated effects. Accordingly, the response of peritoneal macrophages from GM-CSF-deficient mice to LPS was studied in vitro. LPS-stimulated peritoneal macrophages from GM-CSF-deficient mice produced significantly less IL-1alpha and nitric oxide than macrophages from wild-type mice, although there was no difference in TNF-alpha production. Collectively, these observations indicate that GM-CSF contributes to cytokine production in LPS-mediated septic shock, and that the attenuated production of these secondary cytokines (IFN-gamma, IL-1alpha, and IL-6) may contribute to the endotoxin-resistant phenotype of GM-CSF-deficient mice.
Basu
S
S
Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Royal Melbourne Hospital, Victoria, Australia. basu@licre.ludwig.edu.au
Dunn
A R
AR
Marino
M W
MW
Savoia
H
H
Hodgson
G
G
Lieschke
G J
GJ
Cebon
J
J
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D007113:Immunity, Innate; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D012772:Shock, Septic / Q000097:blood / Q000276:immunology / Q000401:mortality
D016207:Cytokines; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor