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to Inhibit Cytokine-Dependent IFN-
Production: Consequences for Reversal of Lipopolysaccharide Desensitization1
Institute of Medical Immunology, Charité, Humboldt-University Berlin, Berlin Germany
LPS hyporesponsiveness is characterized by a diminished production of proinflammatory cytokines which can be caused by pretreatment with either LPS (=LPS desensitization) or the combination of the anti-inflammatory cytokines IL-10 and TGF-
. However, the resulting hyporesponsive states differ regarding their reversibility by the IFN-
-inducing cytokine IL-12. Therefore, we aimed at studying the reasons for this differential IL-12 responsiveness of IFN--producing cells and its consequences for LPS hyporesponsiveness in more detail. In an in vitro IL-12/IL-18 responsiveness model, we demonstrated that IL-10, if permanently present, does not directly inhibit IL-12/IL-18 responsiveness in T/NK cells but indirectly interferes with IFN- production in the presence of monocytes. In contrast, TGF- acted directly on IFN--producing cells by interfering with IL-12/IL-18 responsiveness. After removal of IL-10 but not of TGF-, LPS hyporesponsiveness can be reverted by IL-12/IL-18. Consequently, the addition of recombinant TGF- during LPS desensitization rendered PBMCs hyporesponsive to a reversal by IL-12/IL-18. Our data suggest that the persistence of IL-10 and the presence of TGF- determine the level of IFN- inhibition and may result in different functional phenotypes of LPS desensitization and LPS hyporesponsiveness in vitro and in vivo.
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