Characterization of a powerful high affinity antagonist that inhibits biological activities of human interleukin-13.
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.
Oshima
Y
Y
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, USA.
Puri
R K
RK
D000595:Amino Acid Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015847:Interleukin-4 / Q000737:chemistry; D015848:Interleukin-5 / Q000737:chemistry; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D018793:Interleukin-13; D015848:Interleukin-5; D018950:Lipopolysaccharide Receptors; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor