title: TNFR2 maintains adequate IL-12 production by dendritic cells in inflammatory responses by regulating endogenous TNF levels.
abstract: Sepsis-induced immune reactions are reduced in TNF receptor 2 (TNFR2)-deficient mice as previously shown. In order to elucidate the underlying mechanisms, the functional integrity of myeloid cells of TNFR2-deficient mice was analyzed and compared to wild type (WT) mice. The capacity of dendritic cells to produce IL-12 was strongly impaired in TNF-deficient mice, mirroring impaired production of IL-12 by WT dendritic cells in sepsis or after LPS or TNF pre-treatment. In addition, TNFR2-deficient mice were refractory to LPS pre-treatment and also to hyper-sensitization by inactivated Propionibacterium acnes, indicating habituation to inflammatory stimuli by the immune response when TNFR2 is lacking. Constitutive expression of TNF mRNA in kidney, liver, spleen, colon and lung tissue, and the presence of soluble TNFR2 in urine of healthy WT mice supported the conclusion that TNF is continuously present in naïve mice and controlled by soluble TNFR2. In TNFR2-deficient mice endogenous TNF levels cannot be balanced and the continuous exposure to enhanced TNF levels impairs dendritic cell function. In conclusion, TNF pre-exposure suppresses secondary inflammatory reactions of myeloid cells; therefore, continuous control of endogenous TNF by soluble TNFR2 seems to be essential for the maintenance of adequate sensitivity to inflammatory stimuli.
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Martin
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Remke
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Pfeifer
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Polz
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Pietryga-Krieger
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Steffens-Weber
authors.affiliation: Max-Planck-Institute for Immunobiology, Freiburg, Germany.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Freudenberg
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mostböck
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany daniela.maennel@klinik.uni-regensburg.de.
authors.forename: Daniela N
authors.initials: DN
authors.lastname: Männel
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D007249:Inflammation / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011425:Propionibacterium acnes / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12
keywords: Tolerance; immune suppression; inflammation; tumor necrosis factor