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Interaction between Transmembrane TNF and TNFR1/2 Mediates the Activation of Monocytes by Contact with T Cells¹

Manuela Rossol^*, Undine Meusch^*, Matthias Pierer^*, Sylke Kaltenhäuser^*, Holm Häntzschel^*, Sunna Hauschildt and Ulf Wagner^2,*

^* Department of Medicine IV, University of Leipzig, Leipzig, Germany; and Department of Immunobiology, Institute of Biology II, University of Leipzig, Leipzig, Germany

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- implies that the interaction between transmembrane TNF- (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--blocking Ab was found to significantly decrease TNF- production by monocytes. Several lines of evidence indicated that signaling through TNFR1/2 and through mTNF (reverse signaling) is involved in TNF- production by monocytes after T cell contact: 1) blocking mTNF on activated T cells leads to a significant reduction in TNF- production; 2) down-regulation of TNFR1/2 on monocytes by transfection with small interfering RNA results in diminished TNF- production; 3) blocking or down-regulating TNFR2 on activated T cells inhibits TNF- 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- production due to reverse signaling by mTNF; and 5) ligation of mTNF on monocytes by a soluble TNFR2:Ig receptor construct induces TNF- production due to reverse signaling. In conclusion, we identified mTNF and TNFR1/2 as interaction partners contributing to TNF- production in monocytes. Both pathways initiated by mTNF-TNFR interaction are likely to be inhibited by treatment with anti-TNF- Abs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The work presented in this study was supported by grants from the German Ministry for Education and Science (Interdisziplinäres Zentrum für Klinische Forschung Leipzig, Teilprojekt A 21 and Kompetenznetzwerk Rheuma, Entzündlich-rheumatische Systemerkrankungen, Teilprojekt C2.7).

² Address correspondence and reprint requests to Dr. Ulf Wagner, Department of Medicine IV, University of Leipzig, Liebigstrasse 22, Leipzig, Germany. E-mail address: wagu{at}medizin.uni-leipzig.de

³ Abbreviations used in this paper: RA, rheumatoid arthritis; mTNF, transmembrane TNF; siRNA, small interfering RNA.