Biology Reference
In-Depth Information
TNFα generates its diverse biological effects through binding to two
distinct cell surface receptors of 55-60 kDa (known as p55TNFR,
TNFR1, or CD120a) and of 75-80 kDa (p75TNFR, TNFR2, or
CD1120b). It is believed that p55TNFR is the principal receptor,
whereas p75TNFR is responsible for increasing the local concentration
of TNFα and passing it on to p55TNFR once the ligand has been bound.
p75TNFR is able to play its supportive role due to its higher affinity for
TNFα compared with p55TNFR (K
d
= 0.1
×
10
-9
M
vs.
0.5
×
10
-9
M,
respectively). TNFR1 is found on all nucleated cells, while TNFR2 is
only expressed on hematopoietic cells. The binding of TNFα to TNFR1
initiates a kinase cascade that leads to the activation of members of the
mitogen-activated protein kinase (MAPK) family: extracellular signal-
regulated kinases (ERKs),
jun
terminal kinase-1 (JNK-1 or stress-
activated protein kinase-1), and p38/stress-activated protein kinase-2
(p38/SAPK-2). These kinases activate the transcription factors Elk-1,
ATF2, c-jun, and NF-κB, which results in the secretion of other
cytokines, expression of adhesion molecules, and production of
proteases. Both TNF receptor types, after the initial response to
cytokines, are shed from host cells and the soluble p55 and p75 receptors
become natural inhibitors of TNFα and help clear the cytokine from the
host.
The soluble TNFα, which exists as a compact bell-shaped
noncovalently linked homotrimer, recruits several other phagocytic cells
after release in an attempt to clear the pathogen, and through a series of
events involving several cytokines, also induces inflammation, fever, and
hypotension. An X-ray defraction analysis of the human TNFβ trimer
attached to TNFR1 has revealed that the ligand-receptor interaction
occurs mainly at the grooves between the TNFβ monomers, which
explains why TNFα and TNFβ monomers are not bioactive (Smith
et al.
,
1994).
6.1.3.2
Potential for anticancer therapy
Ever since the initial discovery of TNFα's antitumor activity, numerous
groups have reported its use in several Phase I and II clinical trials
against a variety of tumor types including sarcoma, colorectal carcinoma,
