Mechanism of action of interleukin-13 antagonist (IL-13E13K) in cells expressing various types of IL-4R.

Abstract

As interleukin (IL)-13 and IL-4 play a major role in various diseases including asthma, allergy, and malignancies, it is desirable to generate a molecule that blocks the effects of both cytokines. We previously generated a human IL-13 mutant (IL-13E13K), which is a powerful antagonist of IL-13, blocking the biological activities of IL-13. We now show that IL-13E13K also competitively inhibits signaling and biological activities of IL-4 through type II and partially through type III IL-4 receptor (R) system. IL-13E13K completely blocked the IL-4-induced phosphorylation of STAT6 and IL-4-dependent protein synthesis in cells expressing type II and partially type III IL-4R but not type I IL- 4R. Consistent with the inhibition of biological activities, IL-13E13K inhibited IL-4 binding to type II IL-4R-expressing cells but not to type I IL-4R-expressing cells. The inhibition efficiency of IL-4 binding by IL-13E13K was relatively lower compared to wtIL-13 even though IL-13E13K bound to IL-13Ralpha1 positive cells with a similar affinity to wtIL-13. These results indicate that Glu13 in IL-13 associates with IL-4Ralpha, and mutation to lysine decreases its binding ability to IL-4Ralpha chain. IL-13E13K binds to IL- 13Ralpha1, which is shared by both IL-13R and IL-4R systems. Consequently, IL-13E13K inhibits IL-4 binding to these cells and prevents heterodimer formation between IL-13Ralpha1 and IL-4Ralpha chains. This interference by IL-13E13K blocks the biological activities of not only IL-13 but also partially of IL-4. Thus, IL-13E13K may be a useful agent for the treatment of diseases such as asthma, allergic rhinitis, and cancer, which are dependent on signaling through both IL-4 and IL-13 receptors.

• Authors: Mitomu Kioi, Koji Kawakami, Raj K Puri
• Journal: Cellular immunology (Cell Immunol) Vol. 229 Issue 1 Pg. 41-51 (May 2004) ISSN: 0008-8749 [Print] Netherlands
• PMID: 15331327 (Publication Type: Journal Article)

Chemical References

• Bacterial Toxins
• Exotoxins
• Interleukin-13
• Receptors, IgE
• Receptors, Interleukin-4
• interleukin 13 antagonist E13K
• interleukin-4-Pseudomonas exotoxin
• Interleukin-4

Topics

• Animals
• B-Lymphocytes (metabolism)
• Bacterial Toxins (metabolism)
• COS Cells
• Chlorocebus aethiops
• Exotoxins (metabolism)
• Humans
• Interleukin-13 (antagonists & inhibitors, metabolism)
• Interleukin-4 (metabolism)
• Jurkat Cells
• Protein Biosynthesis (physiology)
• Receptors, IgE (biosynthesis)
• Receptors, Interleukin-4 (metabolism)
• Signal Transduction (physiology)