Transmembrane TNF- : structure, function and interaction with anti-TNF agents

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.

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

“…37 Inflammatory bowel diseases are characterized by substantial leucocyte infiltration 38 with various cells expressing transmembrane TNF. 39 Increase in V may therefore be explained by retention of the monoclonal antibody by cellular TNF. A similar phenomenon was reported for another monoclonal antibody, rituximab (an anti-CD20 monoclonal antibody): its volume at steady-state (Vss) was 6.6 L, 5.6 L and 13.5 L, in RA, 40 follicular non-Hodgkin lymphomas 41 and diffuse large-cell lymphomas, 42 respectively.…”

Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

“…TNF is a proinflammatory cytokine that plays a critical role in inflammation and immunity by binding to TNFRs [97]. TNF functions as a transmembrane protein (to transmit signals as either a ligand or as a receptor) and as a soluble protein (ligand) following shedding by ADAM17 [97].…”

“…TNF is a proinflammatory cytokine that plays a critical role in inflammation and immunity by binding to TNFRs [97]. TNF functions as a transmembrane protein (to transmit signals as either a ligand or as a receptor) and as a soluble protein (ligand) following shedding by ADAM17 [97]. The type I integral membrane glycoprotein, CD27, is another member of the TNFR superfamily with important roles in immunity and tolerance [98].…”

Synthesis and biological evaluation of pyranoisoflavone derivatives as anti-inflammatory agents

“…Cytokines are directly implicated in the processes of inflammation, such as interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). TNF-α, a pro-inflammatory cytokine synthesized as a membrane-bound protein which can be cleaved by proteases to soluble form, is commonly released by macrophages and lymphocytes, and plays a very important role in the inflammatory cascades through activating nuclear factor-κB (NF-κB) [2,3]. Overexpression of cytokines is responsible for a number of inflammatory pathological conditions such as asthma, colitis, hepatitis and rheumatoid arthritis (RA).…”