Biomedical Engineering Reference
In-Depth Information
9.5 Tumour necrosis factors
The TNF family of cytokines essentially consists of two related regulatory factors: TNF-
α
(cachectin) and TNF-β (lymphotoxin). Although both molecules bind the same receptor and in-
duce very similar biological activities, they display limited sequence homology. The human TNF-
α and -β genes are located adjacent to each other on chromosome 6, being separated by only 1100
base pairs. Both contain three introns, and their expression appears to be coordinately regulated.
TNF-
, sometimes referred to simply as TNF, has been studied in signifi cantly greater detail than
lymphotoxin.
α
9.5.1 Tumour necrosis factor biochemistry
TNF-
is also known as cachectin, macrophage cytotoxic factor, macrophage cytotoxin
and necrosin. As some of these names suggest, activated macrophages appear to represent
the most signifi cant cellular source of TNF-
α
, but it is also synthesized by many other cell
types (Table 9.5). Producer cells do not store TNF-α, but synthesize it
de novo
following
activation.
Human TNF-
α
is initially synthesized as a 233 amino acid polypeptide that is anchored in the
plasma membrane by a single membrane-spanning sequence. This TNF pro-peptide, which itself
displays biological activity, is usually proteolytically processed by a specifi c extracellular metallo-
protease. Proteolytic cleavage occurs between residues 76 (Ala) and 77 (Val), yielding the mature
(soluble) 157 amino acid TNF-
α
α
polypeptide. Mature human TNF-
α
appears to be devoid of a
carbohydrate component, and contains a single disulfi de bond.
Monomeric TNF is biologically inactive; the active form is a homotrimer in which the three
monomers associate non-covalently about a threefold axis of symmetry, forming a compact bell-
shaped structure. X-ray crystallographic studies reveal that each monomer is elongated and char-
acterized by a large content of antiparallel
β
pleated sheet, which closely resembles subunit pro-
teins of many viral caspids (Figure 9.4).
A number of stimuli are known to act as inducers of TNF production (Table 9.6). Bacterial LPS
represents the most important inducer, and TNF mediates the pathophysiological effects of this
molecule. TNF biosynthesis is regulated by both transcriptional and post-transcriptional mecha-
nisms. Macrophages appear to express TNF-
α
mRNA constitutively, which is translated only
Table 9.5
The major cellular sources of human TNF-
β
. As is evident, TNF-
α
synthesis is not restricted to cells of the immune system, but is undertaken by
a wide variety of different cells in different anatomical locations, including the
brain
Macrophages
NK cells
Eosinophils
Hepatic Kupffer cells
Glomerular mesangial cells
Fibroblasts
B- and T-lymphocytes
Polymorphonuclear leukocytes
Astrocytes
Langerhan's cells
Brain microglial cells
Various transformed cell lines
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