Transmembrane
TNF-alpha, a precursor of the soluble form of
TNF-alpha, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by
TNF-alpha-converting enzyme (TACE), the soluble form of
TNF-alpha is cleaved from transmembrane
TNF-alpha 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-alpha, but also transmembrane
TNF-alpha is involved in the inflammatory response. Transmembrane
TNF-alpha 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-alpha on
TNF-alpha-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a
ligand, whereas transmembrane
TNF-alpha 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-alpha, but exert different effects on transmembrane
TNF-alpha-expressing cells (
TNF-alpha-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-alpha in granulomatous
inflammation, reviewing the biology of transmembrane
TNF-alpha and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities.