Allergy and Asthma: What 'drives' IL-4 versus IL-13 signalling?
The way in which the IL-4R –IL-13R1 receptor heterodimer affects different responses to IL-4 versus IL-13 has now been explained by both structural and kinetic data.
Interleukin-4 (IL-4) and IL-13 are crucially involved in the development of allergic responses through their induction of T helper 2 (TH2) cells and promotion of IgE production. Both of these cytokines use the common  -chain (c)-related IL-4 receptor -chain (IL-4R) to signal through three cytokine–receptor combinations: IL-4 signals through the type I receptor IL-4R–c, and both IL-4 and IL-13 can signal through the type II receptor IL-4R–IL-13R1. This study describes the crystal structures of these three ligand–receptor combinations, which provide insights into the mechanisms and consequences of receptor degeneracy versus specificity.
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The overall structures of IL-4 and IL-13 and their receptors were similar to the canonical architecture that has been resolved for other cytokine–receptor complexes, with the exception of an extra amino-terminal immunoglobulin-like domain (D1) in IL-13R1 that forms sheet-like contacts with the dorsal surfaces of both IL-4 and IL-13 in the type II receptor. A hydrophobic patch on the surface of IL-13, but not IL-4, forms an additional contact with an apposing hydrophobic patch on D1 of IL-13R1; this might explain why D1 is known to be required for binding and signalling by IL-13 but not IL-4.
The authors also looked at the thermodynamics of complex assembly using soluble receptor extracellular domains. Whereas IL-4 binds first to IL-4R (the 'driver') followed by recruitment of either c or IL-13R1 (the 'triggers'), IL-13 binds first to IL-13R1 (the 'driver') followed by recruitment of IL-4R (the 'trigger'). Two charged residues in IL-4 that are crucial for its interaction with IL-4R are similarly present in IL-13, but the IL-13–IL-4R interface lacks other interactions around the charged residues that were observed at the IL-4–IL-4R interface. This explains why IL-13 must first recruit IL-13R1 to strengthen the interaction with IL-4R. The IL-13–IL-13R1 driver has a high affinity for the IL-4R trigger compared with the low affinity of the IL-4–IL-4R driver for either c or IL-13R1 triggers. The IL-13 receptor complex is therefore more stable than the IL-4 receptor complexes, and the authors suggest that recruitment of the triggers is energetically limiting for IL-4 complexes, which could affect the different signalling properties of IL-4 and IL-13.
Both cytokines induce phosphorylation of signal transducer and activator of transcription 6 (STAT6), but in human cell lines, IL-4 could stimulate STAT6 phosphorylation at significantly lower doses than IL-13, and the response to IL-13 was markedly slower. This would seem to contradict the thermodynamic data showing that recruitment of the trigger receptor IL-4R in IL-13 signalling is more energetically favourable than recruitment of the converse trigger receptor IL-13R1 in IL-4 signalling. However, this could be explained if the number of IL-4R chains was limiting compared with the number of IL-13R1 chains, which seems to be the case in the cell lines that were analysed.
So, the structural and kinetic data provide insights into how the same type II heterodimer (IL-4R–IL-13R1) can respond to different ligands (IL-4 and IL-13) with different signalling potencies and kinetics.
Kirsty Minton
References
- LaPorte, S. L. et al. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 132, 259–272 (2008) | Article | PubMed |
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