Characterization of a powerful high affinity antagonist that inhibits biological activities of human interleukin-13.

Abstract

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.

• Authors: Y Oshima, R K Puri
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 18 Pg. 15185-91 (May 04 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11278629 (Publication Type: Journal Article)

Chemical References

• Interleukin-13
• Interleukin-5
• Lipopolysaccharide Receptors
• Interleukin-4
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Amino Acid Sequence
• Cell Division (drug effects)
• Cell Line
• Cytotoxicity, Immunologic (drug effects)
• Down-Regulation (drug effects)
• Granulocyte-Macrophage Colony-Stimulating Factor (chemistry)
• Humans
• Interleukin-13 (antagonists & inhibitors, chemistry)
• Interleukin-4 (chemistry)
• Interleukin-5 (chemistry)
• Lipopolysaccharide Receptors (metabolism)
• Models, Molecular
• Molecular Sequence Data
• Protein Conformation
• Sequence Homology, Amino Acid