Biology Reference
In-Depth Information
in an assortment of diseases including most notably bacterial sepsis.
Sepsis, which causes over 200,000 deaths per year, is characterized by a
systemic pro-inflammatory response to the lipid A component of
lipopolysaccharide (LPS) in Gram-negative bacteria and to lipoteichoic
acid, peptidoglycan, and exotoxins of Gram-positive bacteria. In
addition, chronic over-expression of TNFα has been linked to
inflammatory diseases such as cachexia, diabetes, rheumatoid arthritis,
and Crohn's disease.
The antitumor properties of TNFα include direct necrosis of solid
tumors
in vitro
and disruption of the tumor vasculature
in vivo
. In fact,
one of the earliest successful human cancer treatments involved
administering
E. coli
extracts containing LPS to patients, presumably a
regimen that involved stimulation of the secretion of non-lethal doses of
TNFα
in vivo
. Similar TNFα secretion dose-response curves upon
exposure of human peripheral blood mononuclear cells (hPBMC's) to
either some specific ellagitannins or to LPS have raised the question of
whether the tannins may be achieving their documented tumoricidal
action through the well-studied LPS/lipid A cellular receptor system.
Consequently, the potential for ellagitannins to act as lipid A
agonists
(
i.e.
, mimicking LPS/lipid A activity), and the prospects for redesigning
the ellagitannin structure to develop a lipid A
antagonist
(
i.e.
,
counteracting LPS/lipid A activity) are under study.
6.1.1 Lipid A
The outer surface of the outer membrane of the cell wall of Gram-
negative bacteria is composed primarily of the amphipathic glycolipid
lipopolysaccharide (Nikaido and Vaara, 1985).
LPS (also known as
endotoxin and enteric LPS) is the major surface-associated antigen for
several Gram-negative bacteria and is involved in several pathological
activities associated with the immune response of the human host
(Meredith
et al.
, 2006).
A single
E. coli
cell contains around 2 to 4
million LPS molecules. They are highly heat-stable, as a temperature of
about 180 °C is needed to inactivate endotoxins.
