A novel Mutein of TNFα Containing the Arg-Gly-Asp Sequence Shows Reduced Toxicity in Intestine
The effects of human tumour necrosis factor-α (TNFα), or its mutein (F4168) having the cell adhesive Arg-Gly-Asp sequence at the N-terminus, on intestinal injury, were examined. Histopathological examination revealed that an intravenous injection of TNFα resulted in marked haemorrhage or oedema in t...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
1994-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/S096293519400013X |
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| Summary: | The effects of human tumour necrosis factor-α (TNFα), or its
mutein (F4168) having the cell adhesive Arg-Gly-Asp sequence at the
N-terminus, on intestinal injury, were examined. Histopathological
examination revealed that an intravenous injection of TNFα
resulted in marked haemorrhage or oedema in the caecum of rats,
whereas F4168 showed no such effects even at the same therapeutic
dose. Moreover, the number of neutrophils that adhered to
endothelial cells or infiltrated the mucosal tissue was much higher
after TNFα injection compared with F4168 in vivo.
The enhanced adhesion of neutrophils on to human umbilical vein
endothelial cells also occurred when the latter were pre-stimulated
with TNFα but not with F4168 in vitro. The
expression of the cell adhesion molecules including endothelial
leukocyte adhesion molecule-1 or intercellular adhesion molecule-1
on F4168- stimulated human umbilical vein endothelial ceils was
significantly lower than that stimulated with TNFα. These
results suggest that the Arg-Gly-Asp sequence introduced into the
TNFα molecule abrogates the side effect of this cytokine such
as tissue injury or shock, and that F4168 could be useful for
systemic therapy. |
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| ISSN: | 0962-9351 1466-1861 |