Effect of IL-13 receptor α2 levels on the biological activity of IL-13 variant R110Q

Background: IL-13 is a key cytokine associated with the asthmatic phenotype. IL-13 signals via its cognate receptor, a complex of IL-13 receptor (11,4311) a I chain with IL-4 receptor a; however, a second protein, 11,IL-13R alpha 2, also binds IL-13. Recently a polymorphic variant of IL-13 (R110Q) has been shown to be associated with atopy. Objective: To investigate the binding properties of this IL-13 variant to its cognate receptors. Methods: We used surface plasmon resonance to measure the binding kinetics of R110Q to its receptors. Primary human fibroblasts were grown from endobronchial biopsies obtained from volunteers. Receptor levels were measured by fluorescence-activated cell sorting. Results: There was no significant difference in the binding of R110Q with soluble human IL-13R alpha 1 compared with IL-13 (32 +/- 5 nmol/L and 36 +/- 7 nmol/L, respectively; P =.625). However, a small but significant difference was observed in the binding of R110Q to soluble human 11,IL-13R alpha 2 compared with IL-13 (840 +/- 87 pmol/L and 1.1 +/- .05 nmot/L, respectively; P =.04). We observed that primary human lung fibroblasts expressed different levels of 11,IL-13R alpha 2. Eotaxin release from fibroblasts expressing low IL-13R alpha 2 levels was significantly higher in response to R110Q compared with IL-13. This was not evident in cells that had high baseline 11,IL-13R alpha 2 levels. Conclusion: These results suggest that relatively small changes in functional properties of a ligand combined with variation in receptor levels in vivo can result in significant differences in responsiveness. Clinical implications: Expression of R110Q and low IL-13R alpha 2 levels can result in important biological differences that may have clinical relevance in an atopic environment.