Effect of IL-13 receptor alpha2 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 (IL-13R) alpha 1 chain with IL-4 receptor alpha; however, a second protein, IL-13Ralpha2, 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-13Ralpha1 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 IL-13Ralpha2 compared with IL-13 (840 +/- 87 pmol/L and 1.1 +/- .05 nmol/L, respectively; P = .04). We observed that primary human lung fibroblasts expressed different levels of IL-13Ralpha2. Eotaxin release from fibroblasts expressing low IL-13Ralpha2 levels was significantly higher in response to R110Q compared with IL-13. This was not evident in cells that had high baseline IL-13Ralpha2 levels.


CONCLUSIONS
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.


CONCLUSIONS
Expression of R110Q and low IL-13Ralpha2 levels can result in important biological differences that may have clinical relevance in an atopic environment.
Andrews
Allison-Lynn
AL
Infection, Inflammation and Repair Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
Bucchieri
Fabio
F
Arima
Kazuhiko
K
Izuhara
Kenji
K
Holgate
Stephen T
ST
Davies
Donna E
DE
Holloway
John W
JW
D000328:Adult; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism*; D007700:Kinetics; D020641:Polymorphism, Single Nucleotide; D050800:STAT6 Transcription Factor / Q000378:metabolism; D020349:Surface Plasmon Resonance
D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053663:Interleukin-13 Receptor alpha2 Subunit; D050800:STAT6 Transcription Factor