H. Shikama et al., A NOVEL MUTEIN OF TNF-ALPHA CONTAINING THE ARG-GLY-ASP SEQUENCE SHOWSREDUCED TOXICITY IN INTESTINE, Mediators of inflammation, 3(2), 1994, pp. 111-116
The effects of human tumour necrosis factor-alpha (TNF alpha), or its
mutein (F4168) having the cell adhesive Arg-Gly-Asp sequence at the N-
terminus, on intestinal injury, were examined Histopathological examin
ation revealed that an intravenous injection of TNF alpha resulted in
marked haemorrhage or oedema in the caecum of rats, whereas F4168 show
ed no such effects even at the same therapeutic dose. Moreover, the nu
mber of neutrophils that adhered to endothelial cells or infiltrated t
he mucosal tissue was much higher after TNF alpha injection compared w
ith F4168 in vivo. The enhanced adhesion of neutrophils on to human um
bilical vein endothelial cells also occurred when the latter were pre-
stimulated with TNF alpha but not with F4168 in vitro. The expression
of the cell adhesion molecules Including endothelial leukocyte adhesio
n molecule-1 or intercellular adhesion molecule-1 on F4168- stimulated
human umbilical vein endothelial cells was significantly lower than t
hat stimulated with TNF alpha. These results suggest that the Arg-Gly-
Asp sequence introduced into the TNF alpha molecule abrogates the side
effect of this cytokine such as tissue injury or shock, and that F416
8 could be useful for systemic therapy.