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.
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.
Y
Y
Oshima
R K
RK
Puri
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