Published online before print November 11, 2003

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(Journal of Leukocyte Biology. 2004;75:324-331.)
© 2004 by Society for Leukocyte Biology

LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway

Silvia Kirchner^*, Simone Boldt, Walter Kolch^,, Silvia Haffner^*, Seran Kazak^*, Petra Janosch, Ernst Holler^*, Reinhard Andreesen^* and Günther Eissner^*,1

^* Department of Hematology and Oncology, University of Regensburg, Germany; and
The Beatson Institute for Cancer Research and the
University of Glasgow, Scotland, United Kingdom

¹ Correspondence: Department of Hematology and Oncology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany. E-mail: guenther.eissner{at}klinik.uni-regensburg.de

The transmembrane form of tumor necrosis factor (mTNF), expressed on activated monocytes (MO) and macrophages (M), is able to induce apoptosis in human endothelial cells (EC). Apoptosis is mediated by two distinct mechanisms: direct cell contact and a yet-unidentified soluble protein, death factor X. In addition, mTNF acts as a receptor that transduces a "reverse signal" into MO/M when bound to the TNF receptor on EC. Reverse signaling by mTNF confers resistance to bacterial lipopolysaccharide (LPS). Stimulation of reverse signaling by mTNF blocks the ability of MO/M to produce death factor X and proinflammatory cytokines. We have investigated which signaling pathways are used by mTNF acting as receptor. Reverse signaling triggers two independent pathways that can be distinguished by protein kinase C (PKC) inhibitors. The suppression of LPS-induced death factor X is dependent on PKC, whereas the suppression of LPS-mediated cytokine release is not. LPS and reverse signaling stimulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. It is interesting that the activation of reverse signaling by mTNF renders MO/M refractory to a subsequent activation of the MAPK/ERK pathway by LPS. Thus, reverse signaling achieves LPS resistance in monocytic cells through interference with key signal-transduction pathways.

Key Words: signal transduction • endotoxin • bidirectional cytokine signaling

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