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An immune cell-selective interleukin 4 agonist

By Armen B. Shanafelt, Carla P. Forte, James J. Kasper, Lisa Sanchez-Pescador, Monte Wetzel, Robert Gundel and Jeffrey M. Greve

Abstract

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

Topics: Biological Sciences
Publisher: The National Academy of Sciences
Year: 1998
DOI identifier: 10.1073/pnas.95.16.9454
OAI identifier: oai:pubmedcentral.nih.gov:21359
Provided by: PubMed Central
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