Mechanisms of asthma and allergic inflammationEffect of IL-13 receptor α2 levels on the biological activity of IL-13 variant R110Q
Section snippets
Reagents
CM5 sensor chip, HBS buffer (10 nmol/L HEPES with 0.15 mol/L NaCl, 3.4 mmol/L EDTA, and 0.005% surfactant P20), amine coupling kit, and regeneration agents were supplied by BIAcore (Uppsala, Sweden) unless otherwise stated. The extracellular region of IL-13Rα1 and IL-13Rα2 was fused to the Fc portion of hIgG1 to generate a soluble form of these IL-13 receptors (soluble human [sh] IL-13Rα1.Fc, shIL-13α2.Fc). Eotaxin ELISA kit, recombinant shIL-13Rα1.Fc, shIL-13α2.Fc, and neutralizing IL-13Rα2
Kinetic analysis of R110Q
Previous studies have shown that a soluble form of IL-13Rα2 cannot neutralize the effects of R110Q as efficiently as wild-type IL-13.27, 28 Because both receptor levels and ligand affinity are both key factors in the determining the functional outcome of a receptor mediated response, we first evaluated the binding affinity of R110Q for its cognate receptor chains.
The binding kinetics of IL-13 and R110Q to shIL-13Rα1 and shIL-13Rα2 were analyzed in real time by surface plasmon resonance (SPR)
Discussion
Several studies have established a link between genetic factors such as polymorphic variation in components of the IL-4 and IL-13 pathways and the development of allergic inflammation.32, 33, 34 However, it is an understanding of the functional consequences of these variants that will eventually reveal how these genetic susceptibilities translate into the development of asthma or other allergic diseases. Furthermore, when polymorphic variation occurs in more than 1 component of a pathway, as
References (37)
- et al.
Receptors and cytokines involved in allergic TH2 cell responses
J Allergy Clin Immunol
(1999) - et al.
Interleukin 13, an interleukin-4 like cytokine acts on monocytes and B cells but not T cells
Immunol Today
(1994) - et al.
Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex
FEBS Lett
(1997) - et al.
Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15
J Biol Chem
(1995) - et al.
cDNA cloning and characterization of the human interleukin 13 receptor alpha chain
J Biol Chem
(1996) - et al.
Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain
J Biol Chem
(1996) - et al.
Kinetic analysis of the interleukin-13 receptor complex
J Biol Chem
(2002) - et al.
Identification, purification, and characterization of a soluble interleukin (IL)-13-binding protein: evidence that it is distinct from the cloned Il-13 receptor and IL-4 receptor alpha-chains
J Biol Chem
(1997) - et al.
A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE level in three populations of white children
J Allergy Clin Immunol
(2000) - et al.
Associations between specific serum IgE response and 6 variants within the genes IL-4, IL-13 and IL-4RA in German children: the German Multicentre Atopy Study
J Allergy Clin Immunol
(2004)
An IL-13 coding region variant is associated with high total serum IgE and atopic dermatitis in the German Multicentre Atopy Study
J Allergy Clin Immunol
Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma
J Allergy Clin Immunol
IL-13Rα2: a regulator of IL-13 and IL-4 signal transduction
J Allergy Clin Immunol
Genetic polymorphism in allergy and asthma
Curr Opin Immunol
Functional effect of the R110Q Il-13 genetic variant alone and in combination with IL-4RA genetic variants
J Allergy Clin Immunol
Conversion of interleukin into a high affinity agonist by a single amino acid substitution
J Biol Chem
Characterisation of the interaction between interleukin-13 and interleukin-13 receptors
J Biol Chem
Interleukin-13 in asthma pathogenesis
Immunol Rev
Cited by (30)
The Genetics of Allergic Disease and Asthma
2016, Pediatric Allergy: Principles and Practice: Third EditionThe discovery, engineering and characterisation of a highly potent anti-human IL-13 fab fragment designed for administration by inhalation
2013, Journal of Molecular BiologyCitation Excerpt :This supported work by Arima et al. who demonstrated that R130Q variant hIL-13 had a lower affinity for IL-13Rα2 than wild-type hIL-13.10 More recently, Andrews et al. have shown that R130Q variant IL-13 was a potent inducer of eotaxin release and STAT-6 phosphorylation in human lung fibroblasts where expression of IL-13Rα2 was low.49 These studies clearly highlight the importance of neutralising both wild type and R130Q variant hIL-13 with an antibody.
The Genetics of Allergic Disease and Asthma
2010, Pediatric Allergy: Principles and Practice Expert Consult: Second EditionCytokine and cytokine receptor gene polymorphisms and their functionality
2009, Cytokine and Growth Factor ReviewsNew insights into mechanisms of immunoregulation in 2007
2008, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Recently, a polymorphic variant of the IL-13 receptor (R110Q) has been shown to be associated with atopy. Expression of R110Q and low IL-13 receptor α2 levels can result in important biologic differences that might have clinical relevance in an atopic environment.61 Polymorphisms in IL13 are associated with serum total IgE levels and eosinophil counts.62
Advances in asthma and allergy genetics in 2007
2008, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Most importantly, the minor A allele at IL13+2044 (rs20541) was also strongly associated with late, but not early, wheezing, raising the possibility that early and late wheezing after RSV LRTI might be caused by distinct pathophysiologic mechanisms. The effect of IL13+2044GA (rs20541) on IL-13 function was further supported by another study showing increased activity of the IL-13 R130Q protein variant on cells expressing low IL-13 receptor α2 levels.31 Replication of results across studies remains the gold standard to assess the robustness of genetic associations.
A.-L. Andrews is an Asthma UK fellow.
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.