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J. Biol. Chem., Vol. 266, Issue 34, 23128-23134, 12, 1991
I Clark-Lewis, C Schumacher, M Baggiolini and B Moser
Interleukin-8 (IL-8) is an inflammatory mediator that stimulates neutrophil
migration and functional activation. Analogs of human IL-8 were chemically
synthesized, purified, and compared with the full- length 72-residue
synthetic IL-8 for their ability to stimulate neutrophil chemotaxis and
exocytosis as measured by assaying for release of elastase, as well as
their binding to specific receptors in competition assays. Analogs
corresponding to the less abundant natural forms, 3-72, 4-72, and
77-residue IL-8, were evaluated and the 3-72 and 4-72 had 2-5-fold higher
potencies, whereas the 77-residue IL-8 was 2- fold less potent. A major
finding was that NH2-terminal residues 4, 5, and 6 were absolutely
essential for IL-8 activity and receptor binding. Quantitative dissociation
of elastase release and chemotaxis activity was detected with 5-72, which
compared with 1-72, was 80-fold less potent in the elastase assay, but was
only slightly less potent in stimulating chemotaxis. IL-8 6-72 lacked all
the biological activities tested but had detectable receptor binding
activity. The NH2-terminal peptide, AVLPRSAKEL, lacked activity and
receptor binding, suggesting that the NH2-terminal region alone is not
sufficient for function. Comparison of analogs shortened at the COOH
terminus showed that potency was progressively reduced as the COOH-terminal
residues were excluded. However activity was retained in an analog (1-51)
with the entire COOH-terminal alpha helix and beta turn missing. A peptide
corresponding to the COOH-terminal 22 residues, although inactive alone,
synergized with the 1-51 analog in stimulating elastase release. The
results suggest that the NH2-terminal residues 4, 5, and 6, which are
disordered in the IL-8 solution structure, are directly involved in
receptor binding, but the COOH-terminal alpha helix is probably important
for stabilizing the three-dimensional structure. Other regions within
residues 7-51 are also functionally important.
Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities
Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
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