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

Cell Immunol. 2004 May;229(1):41-51. doi: 10.1016/j.cellimm.2004.06.005.

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.

MeSH terms

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

Substances

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