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Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; and
Bayer Corp., Berkeley, CA 94701
The closely related Th2 cytokines, IL-4 and IL-13, share many
biological functions that are considered important in the development
of allergic airway inflammation and airway hyperresponsiveness (AHR).
The overlap of their functions results from the IL-4R 
-chain forming
an important functional signaling component of both the IL-4 and IL-13
receptors. Mutations in the C terminus region of the IL-4 protein
produce IL-4 mutants that bind to the IL-4R -chain with high
affinity, but do not induce cellular responses. A murine IL-4 mutant
(C118 deletion) protein (IL-4R antagonist) inhibited IL-4- and
IL-13-induced STAT6 phosphorylation as well as IL-4- and IL-13-induced
IgE production in vitro. Administration of murine IL-4R antagonist
during allergen (OVA) challenge inhibited the development of allergic
airway eosinophilia and AHR in mice previously sensitized with OVA. The
inhibitory effect on airway eosinophilia and AHR was associated with
reduced levels of IL-4, IL-5, and IL-13 in the bronchoalveolar lavage
fluid as well as reduced serum levels of OVA-IgE. These observations
demonstrate the therapeutic potential of IL-4 mutant protein receptor
antagonists that inhibit both IL-4 and IL-13 in the treatment of
allergic asthma.
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