Granulocyte-Macrophage Colony-Stimulating Factor and IFN-γ Restore the Systemic TNF-γ Response to Endotoxin in Lipopolysaccharide-Desensitized Mice

The influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ on the restoration of impaired TNF-α release in LPS-desensitized mice or their refractory macrophages was investigated. Mice pretreated with GM-CSF or IFN-γ (50 μg/kg i-v.) and injected with 3 mg/kg LPS i.p. displayed increased plasma TNF-α levels compared with LPS controls. IL-10 was marginally up-regulated by GM-CSF but abrogated by IFN-γ pretreatment. LPS-tolerant mice (30 μg/kg LPS i.p., -24 h) showed an attenuated plasma TNF-α and IL-10 response to LPS and survived LPS shock. Pretreatment of such mice with GM-CSF or IFN-γ restored the previously impaired TNF-α response. In cultures of murine monocyte/macrophage-containing cell populations, i.e., alveolar, peritoneal, spleen, bone marrow cells, or blood, the presence of GM-CSF or IFN-γ (10 ng/ml) resulted in an enhanced release of TNF-γ initiated by 1 μg/ml LPS. Cells from LPS-tolerant mice showed a diminished responsiveness to LPS. However, when exposed to GM-CSF or IFN-γ ex vivo, their TNF-γ response to LPS was partially restored. These findings characterize GM-CSF and IFN-γ as potent enhancers of LPS-induced TNF-α production in normal as well as in experimentally immunocompromised mice and provide the rationale for further experiments to explore the pharmacologic use of these cytokines for restoration of immunocompetence in sepsis-associated immunosuppression.