An Immune Cell-Selective Interleukin 4 Agonist

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 16; pp. 9454 - 9458
• Main Authors: Shanafelt, Armen B., Forte, Carla P., Kasper, James J., Sanchez-Pescador, Lisa, Wetzel, Monte, Gundel, Robert, Greve, Jeffrey M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 04-08-1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Agonists; B lymphocytes; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Binding, Competitive; Biological Sciences; Blasts; Cells; Cells, Cultured; Cellular biology; Cytokines; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Humans; Immune system; Interleukin-4 - agonists; Interleukin-4 - metabolism; Monocytes; Pharmacology; Receptors; Receptors, Interleukin-4 - metabolism; Secretion; T lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor necrosis factors; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.16.9454

Interleukin 4 (IL-4) is a pleiotropic cytokine. Of the cell types responsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4Rα /IL-2Rγ (class I IL-4R), whereas endothelial cells express another type, IL-4Rα /IL-13Rα (class II IL-4R). It was hypothesized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. A series of IL-4 muteins were generated that were substituted in the region of IL-4 implicated in interactions with IL-2Rγ . These muteins were evaluated in T cell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological selectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding studies indicated that IL-4/R121E retained physical interaction with IL-2Rγ but not IL-13Rα ; consistent with this observation, IL-4/R121E was an antagonist of IL-4-induced activity on endothelial cells. IL-4/R121E exhibits a spectrum of activities in vitro that suggest utility in the treatment of certain autoimmune diseases.