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Sci. Signal., 23 December 2008
Vol. 1, Issue 51, p. ra17
[DOI: 10.1126/scisignal.1164795]


Editor's Summary

Selective Activation
The T cell–derived cytokines interleukin-4 (IL-4) and IL-13 are closely related and are associated with allergic inflammatory responses, such as those that occur in asthma. IL-4 binds to the IL-4 receptor {alpha} (IL-4R{alpha}) subunit, which heterodimerizes with either the {gamma}C subunit or the IL-13R{alpha}1 subunit to form the type I or type II IL-4 receptors, respectively. Thus, whereas IL-4 activates both type I and type II receptors, IL-13 activates type II receptors. In allergic asthma, IL-4 is important in driving the differentiation of T helper type 2 (TH2) cells, whereas IL-13 plays a role in mucus secretion and airway hyperresponsiveness. Because of their overlap in receptor usage, it has been difficult to tease apart the different contributions of IL-4 and IL-13 (see the Perspective by Wills-Karp and Finkelman). By comparing the responses to each cytokine of a human cell line expressing type I and type II receptors to that of cells expressing only type II receptors, Heller et al. have found a critical difference in the signaling pathways activated by IL-4 and IL-13. Although both cytokines activated signal transducer and activator of transcription 6 to a similar extent, IL-4–stimulated phosphorylation and activation of insulin receptor substrate 2 (IRS-2) was much more efficient than that of IL-13 and was dependent on the presence of the {gamma}C subunit. Moreover, type I IL-4 receptor–mediated activation of IRS-2 resulted in the expression of a subset of genes associated with alternatively activated macrophages. By increasing our understanding of the differences between IL-4– and IL-13–dependent signaling pathways, these data may help in the development of more selective therapies against allergic asthma.

Citation: N. M. Heller, X. Qi, I. S. Junttila, K. A. Shirey, S. N. Vogel, W. E. Paul, A. D. Keegan, Type I IL-4Rs Selectively Activate IRS-2 to Induce Target Gene Expression in Macrophages. Sci. Signal. 1, ra17 (2008).

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