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OP0207 Transmembrane TNF-Alpha Reverse Signaling Leading To TGF-Beta Production Is Selectively Activated by Anti-TNF-Alpha Targeting Molecules
  1. A. Pallai1,
  2. B. Kiss1,
  3. G. Vereb2,
  4. M. Armaka3,
  5. G. Kollias3,
  6. Z. Szekanecz4,
  7. Z. Szondy1
  1. 1Department of Dental Biochemistry
  2. 2Department of Biophysics and Cell Biology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary
  3. 3Institute for Immunology, Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece
  4. 4Department of Rheumatology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary

Abstract

Background Tumor necrosis factor (TNF)-a, a potent pro-inflammatory cytokine, is generated in a precursor form called transmembrane (m)TNF-a that is expressed on the surface TNF-a producing cells. TNF-a was shown to act both as a ligand by binding to TNF-a receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into the mTNF-a bearing cells. Anti-TNF-a targeting molecules which neutralize TNF-a with the same efficiency show disease specific effectiveness.

Objectives The aim of the present study was to characterize mTNF-a signaling and to test whether known anti-TNF-a targeting molecules trigger mTNF-a signaling in human macrophages.

Methods TNF-a expression and localization was studied in mouse bone marrow derived macrophages by RT-QPCR or FACS analysis and confocal microscopy. mTNF-a signaling was triggered by coated anti-TNF-a antibodies and tested by a Phospho-MAPK array. The cytokine induced was determined by RT-QPCR analysis and ELISA. The effect of mTNF-a signaling on lipopolysaccharide (LPS)-induced pro-inflammatory cytokine formation was tested with a cytokine array.

Results Non-activated macrophages express basal levels of mTNF-a and respond to anti-TNF-a antibodies by triggering the mitogen-activated protein kinase kinase 4 signaling pathway leading transforming growth factor (TGF)-b production. Exposure to LPS further induced the expression of mTNF-a, and mTNF-a signaling suppressed the LPS-induced pro-inflammatory response via TGF-b. Since apoptotic cells downregulate their TNF receptors, they do not trigger mTNF-a for TGF-b production. Etanercept, a soluble TNF-a receptor, does not, while golimumab and infliximab, which are anti-TNF-a antibodies, do trigger TGF-b production in human macrophages.

Conclusions Induction of TGF-b production by mTNF-a or by receptors triggered by apoptotic cells could be considered in the therapy of inflammatory diseases and may, in part, also account for differences in the actions of various TNF-a inhibitors.

Disclosure of Interest None declared

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