Mechanism of action of interleukin-13 antagonist (IL-13E13K) in cells expressing various types of IL-4R.
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.
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Mitomu
M
Kioi
Koji
K
Kawakami
Raj K
RK
Puri
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D005098:Exotoxins / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D019169:Jurkat Cells; D014176:Protein Biosynthesis / Q000502:physiology*; D017455:Receptors, IgE / Q000096:biosynthesis; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D001427:Bacterial Toxins; D005098:Exotoxins; D018793:Interleukin-13; D017455:Receptors, IgE; D019948:Receptors, Interleukin-4; C436826:interleukin 13 antagonist E13K; C479467:interleukin-4-Pseudomonas exotoxin; D015847:Interleukin-4