GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND IFN-GAMMA RESTORE THE SYSTEMIC TNF-ALPHA RESPONSE TO ENDOTOXIN IN LIPOPOLYSACCHARIDE-DESENSITIZED MICE

The influence of granulocyte-macrophage colony-stimulating factor (GM- CSF) and IFN-gamma on the restoration of impaired TNF-alpha release in LPS-desensitized mice or their refractory macrophages was investigate d. Mice pretreated with GM-CSF or IFN-gamma (50 mu g/kg i.v.) and inje cted with 3 mg/kg LPS i.p. displayed increased plasma TNF-alpha levels compared with LPS controls. IL-10 was marginally up-regulated by GM-C SF but abrogated by IFN-gamma pretreatment. LPS-tolerant mice (30 mu g /kg LPS i.p., -24 h) showed an attenuated plasma TNF-alpha and IL-10 r esponse to LPS and survived LPS shock. Pretreatment of such mice with GM-CSF or IFN-gamma restored the previously impaired TNF-alpha respons e. In cultures of murine monocyte/macrophage-containing cell populatio ns, i.e., alveolar, peritoneal, spleen, bone marrow cells, or blood, t he presence of GM-CSF or IFN-gamma (10 ng/ml) resulted in an enhanced release of TNF-alpha initiated by 1 mu g/ml LPS. Cells from LPS-tolera nt mice showed a diminished responsiveness to LPS. However, when expos ed to GM-CSF or IFN-gamma ex vivo, their TNF-alpha response to LPS was partially restored. These findings characterize GM-CSF and IFN-gamma as potent enhancers of LPS-induced TNF-alpha production in normal as w ell as in experimentally immunocompromised mice and provide the ration ale for further experiments to explore the pharmacologic use of these cytokines for restoration of immunocompetence in sepsis-associated imm unosuppression.