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J. Biol. Chem., Vol. 276, Issue 18, 15185-15191, May 4, 2001
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From the Laboratory of Molecular Tumor Biology, Division of
Cellular and Gene Therapies, Center for Biologics Evaluation and
Research, Food and Drug Administration, National Institutes of Health,
Bethesda, Maryland 20892
Interleukin-13 (IL-13), a predominantly
Th2-derived cytokine, appears to play a central pathological role in
asthma, atopic dermatitis, allergic rhinitis, some parasitic
infections, and cancer. We hypothesized that an IL-13 antagonist may
have profound therapeutic utility in these conditions. We, therefore,
mutagenized human IL-13 in which Glu at position 13 was substituted by
a Lys residue. This highly purified recombinant IL-13 variant,
IL-13E13K, bound with 4-fold higher affinity to the IL-13 receptor than
wild-type IL-13 but retained no detectable proliferative activity on
the TF-1 hematopoietic cell line. IL-13E13K competitively inhibited IL-13- and IL-4-dependent TF-1 proliferation. It also
inhibited IL-13-induced STAT-6 (signal transduction and activator of
transducer-6) activation in immune cells and cancer cells and reversed
IL-13-induced inhibition of CD14 expression on human primary monocytes.
These results demonstrate that high affinity binding and signal
generation can be uncoupled efficiently in a ligand receptor
interaction. These results also suggest that IL-13E13K may be a useful
antagonist for the treatment of allergic, inflammatory, and parasitic
diseases or even malignancies in which IL-13 plays a central role.
Characterization of a Powerful High Affinity Antagonist That
Inhibits Biological Activities of Human Interleukin-13*
*
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.
To whom correspondence should be addressed: Laboratory of
Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug
Administration, 29 Lincoln Dr., NIH Bldg. 29B, Rm. 2NN10, Bethesda, MD
20892. Tel.: 1-301-827-0471; Fax: 1-301-827-0449; E-mail:
puri@cber.fda.gov.
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