Abstracts (complete list) - Wissenschaft Online

Manuela Rossol, Undine Meusch, Holm Häntzschel, Sunna Hauschildt, Ulf Wagner
Activated CD4 T cells induce TNF production in human
monocytes via reverse signalling of membrane TNF
Activated CD4 T cells are able to activate human monocytes by direct cell-cell contact,
which leads to the production of pro-inflammatory cytokines. This process is believed to
be important in chronic inflammatory diseases like rheumatoid arthritis (RA). Previously,
we described membrane TNF expressed on activated T cells and TNF receptor (TNFR) 1
and 2 expressed on monocytes as ligand/receptor pair responsible for monocyte
activation. Now we propose a second mechanism participating in T cell-monocyte cell
contact, namely reverse signalling of membrane TNF in which TNF acts as a signal
transducing receptor.
Several lines of evidence indicate the involvement of TNF reverse signalling in T cellmediated
monocyte activation. (i) Membrane TNF is expressed on monocytes and
TNFR2 is expressed on activated T cells. (ii) Blockade of TNFR2 on activated CD4 T cells
by antibodies led to a diminished TNF production and Erk phosphorylation in monocytes.
(iii) Resting CD4 T cells transfected with a TNFR2 plasmid induced TNF production in
monocytes. (iv) Knockdown of TNFR2 on CD4 T cells by specific siRNA led to a
decreased TNF production in monocytes. (v) Crosslinking of membrane TNF on
monocytes by a plate-bound TNFR2:Ig construct induced a strong production of TNF.
This TNF production depends on activation of MAP kinase Erk and casein kinase 1, the
enzyme responsible for TNF phosphorylation.
In conclusion, we identified reverse signalling of membrane TNF as a second pathway
leading to TNF production in T cell-mediated monocyte activation. Accordingly,
monocytes of RA patients treated with an anti-TNF antibody did not respond to
activated T cells of healthy donors, pointing to a possible blockade of membrane TNF
reverse signalling due to the anti-TNF antibody.