Research ArticleCytokine Signaling

Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency

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Sci. Signal.  10 Nov 2015:
Vol. 8, Issue 402, pp. ra114
DOI: 10.1126/scisignal.aab2677

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Modeling cytokine behavior

The use of cytokines, such as interleukin-2 (IL-2) or IL-13, as therapies has been hampered by the fact that many cytokines share receptor subunits on different cell types. Moraga et al. generated recombinant variants of IL-13 with a wide range of binding affinities for the IL-13 receptor. Mathematical modeling of the correlation between the receptor binding affinities of the variants and the extents to which they differentially stimulated early and late cellular responses highlighted aspects of receptor-ligand binding properties that should aid in the development of more effective cytokine therapies.

Abstract

Cytokines dimerize cell surface receptors to activate signaling and regulate many facets of the immune response. Many cytokines have pleiotropic effects, inducing a spectrum of redundant and distinct effects on different cell types. This pleiotropy has hampered cytokine-based therapies, and the high doses required for treatment often lead to off-target effects, highlighting the need for a more detailed understanding of the parameters controlling cytokine-induced signaling and bioactivities. Using the prototypical cytokine interleukin-13 (IL-13), we explored the interrelationships between receptor binding and a wide range of downstream cellular responses. We applied structure-based engineering to generate IL-13 variants that covered a spectrum of binding strengths for the receptor subunit IL-13Rα1. Engineered IL-13 variants representing a broad range of affinities for the receptor exhibited similar potencies in stimulating the phosphorylation of STAT6 (signal transducer and activator of transcription 6). Delays in the phosphorylation and nuclear translocation of STAT6 were only apparent for those IL-13 variants with markedly reduced affinities for the receptor. From these data, we developed a mechanistic model that quantitatively reproduced the kinetics of STAT6 phosphorylation for the entire spectrum of binding affinities. Receptor endocytosis played a key role in modulating STAT6 activation, whereas the lifetime of receptor-ligand complexes at the plasma membrane determined the potency of the variant for inducing more distal responses. This complex interrelationship between extracellular ligand binding and receptor function provides the foundation for new mechanism-based strategies that determine the optimal cytokine dose to enhance therapeutic efficacy.

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