title: Interaction between transmembrane TNF and TNFR1/2 mediates the activation of monocytes by contact with T cells.
abstract: Monocytes and monocytic cells produce proinflammatory cytokines upon direct cell contact with activated T cells. In the autoimmune disease rheumatoid arthritis, the pivotal role of TNF-alpha implies that the interaction between transmembrane TNF-alpha (mTNF) and the TNF receptors (TNFR1 and TNFR2) might participate in the T cell contact-dependent activation of monocytes. Accordingly, treatment of rheumatoid arthritis by administration of a TNF-alpha-blocking Ab was found to significantly decrease TNF-alpha production by monocytes. Several lines of evidence indicated that signaling through TNFR1/2 and through mTNF (reverse signaling) is involved in TNF-alpha production by monocytes after T cell contact: 1) blocking mTNF on activated T cells leads to a significant reduction in TNF-alpha production; 2) down-regulation of TNFR1/2 on monocytes by transfection with small interfering RNA results in diminished TNF-alpha production; 3) blocking or down-regulating TNFR2 on activated T cells inhibits TNF-alpha production, indicating that mTNF on the monocyte surface mediates signaling; 4) ligation of mTNF on monocytes by surface TNFR2 transfected into resting T cells induces TNF-alpha production due to reverse signaling by mTNF; and 5) ligation of mTNF on monocytes by a soluble TNFR2:Ig receptor construct induces TNF-alpha production due to reverse signaling. In conclusion, we identified mTNF and TNFR1/2 as interaction partners contributing to TNF-alpha production in monocytes. Both pathways initiated by mTNF-TNFR interaction are likely to be inhibited by treatment with anti-TNF-alpha Abs.
authors.affiliation: Department of Medicine IV, University of Leipzig, Leipzig, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rossol
authors.forename: Undine
authors.initials: U
authors.lastname: Meusch
authors.forename: Matthias
authors.initials: M
authors.lastname: Pierer
authors.forename: Sylke
authors.initials: S
authors.lastname: Kaltenhäuser
authors.forename: Holm
authors.initials: H
authors.lastname: Häntzschel
authors.forename: Sunna
authors.initials: S
authors.lastname: Hauschildt
authors.forename: Ulf
authors.initials: U
authors.lastname: Wagner
mesh_terms: D019138:Antibodies, Blocking / Q000008:administration & dosage; D002450:Cell Communication / Q000276:immunology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology