INCREASED TOLERANCE TO ENDOTOXIN BY GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR-DEFICIENT MICE

The contribution of granulocyte-macrophage CSF (GM-CSF) to endotoxin-m ediated septic shock has been assessed by treating GM-CSF-deficient mi ce with LPS. Hypothermia and loss in body weight were markedly attenua ted in LPS-treated GM-CSF-deficient mice compared with similarly treat ed control mice; moreover, the levels of circulating IFN-gamma, IL-1 a lpha, and IL-6 were lower in LPS-treated GM-CSF-deficient mice than LP S-treated control mice, intriguingly, the peak levels of TNF-alpha e t o LPS treatment were the same in tile serum of GM-CSF-deficient mice a nd control mice, although in GM-CSF-deficient mice, TNF-alpha persiste d longer, Activation of macrophages by LPS, resulting in expression of cytokines including TNF-alpha and IL-1, is thought to underlie endoto xin-mediated effects, Accordingly, the response of peritoneal macropha ges from CM-CSF-deficient mice to LPS was studied in vitro. LPS-stimul ated peritoneal macrophages from GM-CSF-deficient mice produced signif icantly less IL-alpha and nitric oxide than macrophages from wild-type mice, although there was no difference in TNF-alpha production, Colle ctively, these observations indicate that GM-CSF contributes to cytoki ne production in LPS-mediated septic shock, and that the attenuated pr oduction of these secondary cytokines (IFN-gamma, IL-1 alpha, and IL-6 ) may contribute to the endotoxin-resistant phenotype of GM-CSF-defici ent mice.