Biomedical Engineering Reference
In-Depth Information
•
Enhances vascular leakness by promoting a reorganization of the cytoskeleton of endothelial
cells.
•
Induction of synthesis of various lipid-based infl ammatory mediators, including some prostag-
landins and platelet-activating factor, by macrophages and other cells. Many of these promote
sustained vasodilation and increased vascular leakage.
•
Induction of synthesis of pro-infl ammatory cytokines, such as IL-1 and IL-8.
TNF-α, therefore, promotes various aspects of immunity and infl ammation. Blockage of its
activity, e.g. by administration of anti-TNF-
antibodies, has been shown to compromise the
body's ability to contain and destroy pathogens.
TNF-
α
exhibits cytotoxic effects on a wide range of transformed cells. Indeed, initial interest in
this molecule (and its naming) stems from its anti-tumour activity. These investigations date back
to the turn of the century, when an American doctor, William Coley, noted that tumours regressed
in some cancer patients after the patient had suffered a severe bacterial infection. Although such ob-
servations prompted pioneering scientists to treat some cancer patients by injection with live bacte-
ria, the approach was soon abandoned because many patients died due to the resulting uncontrolled
bacterial infections, before they could be 'cured' of the cancer. The active tumour agent turned out
to be TNF-α (high circulating levels of which were induced by the bacterially derived LPS).
TNF fails to induce death of all tumour cell types. Although many transformed cells are TNF
sensitive, the cytokine exerts, at best, a cytostatic effect on others and has no effect on yet others.
The cytotoxic activity is invariably enhanced by the presence of IFN-
α
. The concurrent presence
of this interferon increases the range of transformed cell types sensitive to TNF-α, and can up-
grade its cytostatic effects to cytotoxic effects. It can also render many untransformed cells, in
particular epithelial and endothelial cells, susceptible to the cytotoxic effects of TNF-α.
TNF-
γ
can mediate death of sensitive cells via apoptosis or necrosis (necrotic death is
characterized by clumping of the nuclear chromatin, cellular swelling, disintegration of intracellular
organelles and cell lysis; apoptotic death is characterized by cellular shrinking, formation of dense
'apoptotic' masses and DNA fragmentation).
In addition to its cytotoxic effects, TNF-
α
appears to regulate the growth of some (non-trans-
formed) cell types. It is capable of stimulating the growth of macrophages and fi broblasts, while
suppressing division of haematopoietic stem cells. The systemic effects of this cytokine on cellular
growth
in vitro
are thus complex and, as yet, only poorly appreciated.
α
9.5.4 Tumour necrosis factor receptors
Two TNF receptor types have been characterized. The type I receptor displays a molecular mass
of 55 kDa, and is known as TNF-R55 (also P-55, TNFR1 or CD120α). The type II receptor
is larger (75 kDa) and is known as TNF-R75 (also P-75, TNFR2 or CD120
). Both receptors
bind both TNF-α and TNF-β. A TNF receptor is present on the plasma membrane of almost all
nucleated cell types, generally in numbers varying from 100 to 10 000. Although virtually all
cells express TNF-R55, the TNF-R75 cell surface receptor distribution is more restricted, this
being most prominent on haematopoietic cells. Differential regulation of expression of these two
β
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