In Vitro Prevention and Reversal of Lipopolysaccharide Desensitization by IFN-γ, IL-12, and Granulocyte-Macrophage Colony-Stimulating Factor

Felix Randow, Wolf Dietrich Döcke, Daniela S. Bundschuh, Thomas Hartung, Albrecht Wendel, Hans Dieter Volk

Research output: Contribution to journalArticlepeer-review

Abstract

LPS tolerance is characterized by a diminished monocytic synthesis of TNF-α and, interestingly, IL-10 after LPS restimulation. We wondered whether granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, and IFN-γ can prevent or reverse this down-regulation of TNF-α and IL-10 production. The LPS-induced TNF-α amounts in desensitized PBMC treated with GM-CSF, IFN-γ, or IL-12 and in naive, non-cytokine-primed cultures were similar, while much more TNF-α was induced in cytokine-primed naive cells. The effect of IL-12 was dependent on the presence of nonmonocytic cells and could be completely blocked with an IFN-γ antiserum. Treatment of LPS-desensitized pure monocytes with IFN-γ or GM-CSF resulted in a very high TNF-α expression and no difference to cytokine-primed naive monocytes was evident any longer. While IFN-γ and IL-12 decreased IL-10 expression in naive PBMC, it was increased by both and by GM-CSF in LPS-tolerant cultures. Again, only IL-12 was dependent on the presence of nonmonocytic cells. For prevention of LPS tolerance, similar results were obtained. Recently, we have shown that IL-10 and TGF-β mediate LPS desensitization in vitro and can be used to establish LPS hyporesponsiveness in the absence of LPS. IFN-γ and GM-CSF prevented and reversed down-regulation of TNF-α and IL-10 synthesis also in the model of IL-10/TGF-β1-induced LPS hyporesponsiveness, while IL-12 was ineffective because of its obvious inability to induce IFN-γ. In summary, after LPS desensitization/hyporesponsiveness, IFN-γ and GM-CSF tended to normalize pro- and anti-inflammatory monocytic behavior. Our results suggest that during LPS desensitization/hyporesponsiveness, monocytes acquire a hitherto unknown functional state with an altered reaction to biologic response modifiers.

Original languageEnglish (US)
Pages (from-to)2911-2918
Number of pages8
JournalJournal of Immunology
Volume158
Issue number6
StatePublished - Mar 15 1997
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'In Vitro Prevention and Reversal of Lipopolysaccharide Desensitization by IFN-γ, IL-12, and Granulocyte-Macrophage Colony-Stimulating Factor'. Together they form a unique fingerprint.

Cite this