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J. Biol. Chem., Vol. 275, Issue 22, 17051-17057, June 2, 2000
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From Based on sequences of immunomodulatory peptides
derived from the heavy chain of HLA Class I, novel immunomodulatory
peptides with increased potency were developed by computer-aided
rational design. Allotrap 1258 was characterized in detail and shown to inhibit cell-mediated immune responses in vitro and
in vivo. Immunomodulatory activity was associated with the
capability of the peptides to modulate heme oxygenase (HO) activity. In
this study we analyzed the effect of Allotrap 1258 on cytokine
expression. Allotrap 1258 inhibited concanavalin A- and
lipopolysaccharide-induced human and mouse tumor necrosis factor (TNF)
production in vitro and in vivo but had no
effect on interleukin (IL)-1, IL-2, IL-4, IL-6, or IL-10 expression.
Experiments with HO-1/KO and iNOS/KO mice showed that Allotrap
1258-mediated inhibition of TNF was independent of HO-1 and iNOS.
Quantitation of TNF protein expression and mRNA steady state levels
demonstrated that Allotrap 1258-mediated inhibition occurred at the
translational level. Deletion of the AU-rich element in the
3'-untranslated region (UTR) of TNF mRNA, a region known to be
involved in TNF mRNA translation, had minimal effect on Allotrap
1258-mediated inhibition. However, replacement of the TNF 3'-UTR with
the human globin 3'-UTR rendered the peptide inactive. This
demonstrates that besides AU-rich elements, other sequences in the
3'-UTR of TNF mRNA are involved in translational control of TNF
expression. Such sequences are necessary for Allotrap 1258-mediated inhibition of TNF production.
Inhibition of Tumor Necrosis Factor mRNA Translation by a
Rationally Designed Immunomodulatory Peptide*
§,,,,,
SangStat, The Transplant Company, Fremont,
California 94555 and the ¶ Laboratory of Molecular Genetics,
Hellenic Pasteur Institute, Athens 11521, Greece
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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