Summary
Biological activities of peptides representing two different regions in the TNF molecule
were investigated. We have earlier reported that one of the peptides studied, TNF
36-62, induced chemotaxis in granulocytes and monocytes. TNF 41-62, a shorter analog
of TNF 36-62, possessed similar chemotactic effects. Both peptides caused a weak enhancement
of LPS -induced IL-6 production and tissue factor activity by monocytes in whole blood.
The third peptide studied, TNF 78-96, was selected from a region located on the opposite
side of the β-sheet sandwich structure of the TNF molecule, and includes the loop
84-88 that has been shown to be involved in TNF receptor interaction. TNF 78-96 possessed
properties quite different from TNF 36-62 and TNF 41-62. It amplified several fold
PMA-induced secretion of elastase, and enhanced significantly PMA-induced secretion
of cathepsin G from the neutrophils, activities which were effectively abolished by
an anti-human TNF antibody. The TNF 78-96 peptide also inhibited LPS-induced TF activity
in monocytes of whole blood, and it abolished the TNF enhancing effect of LPS-induced
TF activty in a dose dependent manner. This suggests that the TNF 78-96 peptide may
bind to the TNF receptor(s), without potentiating the same signals as native TNF.
It may thereby prevent binding of the native TNF and the resultant activation effect
of TNF. It also, at high concentrations, inhibited LPS-induced IL-6 production whereas
it caused a doubling of LPS-induced IL-8 in monocytes and granulocytes in whole blood.
These results clearly show that distinct TNF activities can be induced by peptide
sequences taken from different regions of TNF. The TNF 78-96 peptide might be useful
in downregulation of LPS-induced monocyte activations in vivo.
Keywords
Molecular modelling - TNF peptides - leukocytes - tissue factor
