Biology Reference
In-Depth Information
yeast), malarial parasite antigens, viruses (Sendai,
Herpes simplex
, and
Epstein-Barr), and, most importantly, LPS (Sidhu and Bollon, 1993).
Several known agents are able to down-regulate TNFα production.
These species include cytokines (IL-4, IL-10, and transforming growth
factor-β), prostaglandin E
2
, Iloprost (a prostacycline analog), histamine,
antioxidants (such as
N
-acetylcystine and glutathione), glucocorticoids
(including dexamethasone, cortisol, and danazol), lipoxygenase
inhibitors, and certain drugs (such as pentoxifylline, thalidomide,
ambroxol, and cyclosporin A).
6.1.3.1
TNF
α
generated from LPS exposure: mediator of septic shock
The link between TNFα and LPS goes back more than 100 years. At the
conclusion of the 19
th
century, the New York surgeon William Coley
reported that inoperable tumors could be treated with Gram-negative and
Gram-positive bacteria (Coley, 1896). Carswell and co-workers later
coined the term “tumor necrosis factor” for the cytokine that caused
hemorrhagic necrosis of tumors in animal models injected with LPS
(Carswell
et al.
, 1975, Helson
et al.
, 1975). TNFα is produced by cells
that have been activated by LPS. LPS (via the lipid A component) is
capable of activating a variety of cells including macrophages,
monocytes, fibroblast, astrocytes, Kupffer cells, smooth muscle cells,
keratinocytes, neutrophils, lymphocytes, platelets, microglial cells,
intestinal paneth cells, endothelial, mast cells, natural killer cells, and
tumor cells (Dixon and Darveau, 2005).
TNFα was purified and
characterized by Aggarwal
et al.
(1985). Its crystal structure has been
reported (Jones
et al.
, 1992). At present, there are 13 different members
in the TNF ligand family, including another factor called TNFβ (also
known as lymphotoxin, LTα, or cytotoxin), which has similar cytotoxic
activities to TNFα, since it binds to the same receptors, but it is produced
only by activated T-lymphocytes.
TNFα is first expressed as a 26 kDa (233 amino acids)
transmembrane peptide that is cleaved by the metalloprotease TNF-
alpha-converting-enzyme (TACE) in activated cells to the soluble 17
kDa (157 amino acids) mature protein (Black
et al.
, 1997a). The 26 kDa
pro-peptide also is functional through cell-to-cell contact. The cleaved
