Different modes of IL-10 and TGF-beta to inhibit cytokine-dependent IFN-gamma production: consequences for reversal of lipopolysaccharide desensitization.
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-beta. However, the resulting hyporesponsive states differ regarding their reversibility by the IFN-gamma-inducing cytokine IL-12. Therefore, we aimed at studying the reasons for this differential IL-12 responsiveness of IFN-gamma-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-gamma production in the presence of monocytes. In contrast, TGF-beta acted directly on IFN-gamma-producing cells by interfering with IL-12/IL-18 responsiveness. After removal of IL-10 but not of TGF-beta, LPS hyporesponsiveness can be reverted by IL-12/IL-18. Consequently, the addition of recombinant TGF-beta 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-beta determine the level of IFN-gamma inhibition and may result in different functional phenotypes of LPS desensitization and LPS hyporesponsiveness in vitro and in vivo.
Institute of Medical Immunology, Charité, Humboldt-University Berlin, Berlin, Germany.
Martina
M
Schröder
Christian
C
Meisel
Katharina
K
Buhl
Nina
N
Profanter
Nadine
N
Sievert
Hans-Dieter
HD
Volk
Gerald
G
Grütz
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D003888:Desensitization, Immunologic / Q000379:methods; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000494:pharmacology / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000633:toxicity*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D020382:Interleukin-18; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma