Transmembrane TNF- : structure, function and interaction with anti-TNF agents
Open Access
- 1 March 2010
- journal article
- review article
- Published by Oxford University Press (OUP) in Rheumatology
- Vol. 49 (7), 1215-1228
- https://doi.org/10.1093/rheumatology/keq031
Abstract
Transmembrane TNF-α, a precursor of the soluble form of TNF-α, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-α-converting enzyme (TACE), the soluble form of TNF-α is cleaved from transmembrane TNF-α and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-α, but also transmembrane TNF-α is involved in the inflammatory response. Transmembrane TNF-α acts as a bipolar molecule that transmits signals both as a ligand and as a receptor in a cell-to-cell contact fashion. Transmembrane TNF-α on TNF-α-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a ligand, whereas transmembrane TNF-α also acts as a receptor that transmits outside-to-inside (reverse) signals back to the cells after binding to its native receptors. Anti-TNF agents infliximab, adalimumab and etanercept bind to and neutralize soluble TNF-α, but exert different effects on transmembrane TNF-α-expressing cells (TNF-α-producing cells). In the clinical settings, these three anti-TNF agents are equally effective for RA, but etanercept is not effective for granulomatous diseases. Moreover, infliximab induces granulomatous infections more frequently than etanercept. Considering the important role of transmembrane TNF-α in granulomatous inflammation, reviewing the biology of transmembrane TNF-α and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities.Keywords
This publication has 111 references indexed in Scilit:
- Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humansJCI Insight, 2009
- Influence of reverse signaling via membrane TNF-α on cytotoxicity of NK92 cellsEuropean Journal of Cell Biology, 2009
- Differences in binding and effector functions between classes of TNF antagonistsCytokine, 2009
- TNF‐mediated inflammatory diseaseThe Journal of Pathology, 2007
- Drug Insight: different mechanisms of action of tumor necrosis factor antagonists—passive-aggressive behavior?Nature Clinical Practice Rheumatology, 2007
- A functional M196R polymorphism of tumour necrosis factor receptor type 2 is associated with systemic lupus erythematosus: a case-control study and a meta-analysisAnnals Of The Rheumatic Diseases, 2007
- Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell–natural killer cell crosstalkBlood, 2006
- A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2bNature, 2006
- SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 productionNature, 2006
- Guanidinoethyl sulphonate is a glycine receptor antagonist in striatumBritish Journal of Pharmacology, 2002