Mechanisms of asthma and allergic inflammation
IL-13 receptor α 2: A regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts

https://doi.org/10.1016/j.jaci.2006.06.041Get rights and content

Background

IL-13 and IL-4 share many functional properties as a result of their use of a common receptor complex comprising IL-13 receptor α 1 (IL-13Rα1) and IL-4 receptor α (IL-4Rα). The nonsignaling receptor IL-13 receptor α 2 (IL-13Rα2) binds IL-13 with high affinity and specificity and is believed to be a decoy receptor for IL-13.

Objective

We sought to examine the inhibitory effects of soluble and membrane-bound IL-13Rα2 on IL-13– and IL-4–mediated effects.

Methods

Primary human fibroblasts were grown from endobronchial biopsy specimens obtained from volunteers. Upregulation of IL-13Rα2 mRNA was measured by means of RT-PCR, and the level of surface expression was measured by means of FACS.

Results

We found that a recombinant soluble form of IL-13Rα2 blocked the effects of IL-13, but not IL-4, in fibroblasts in vitro. However, we found that the transmembrane form of IL-13Rα2 could attenuate both IL-13 and IL-4 responses, even though the response to TNF-α was unaffected. Furthermore, we found that IL-13Rα2 became associated with IL-4Rα in the presence of IL-4. Addition of a blocking antibody to the extracellular domain of IL-13Rα2 restored responses of both IL-13 and IL-4.

Conclusion

The ability of IL-13Rα2 to regulate IL-4 was previously unrecognized in primary airway cells. These data reveal a novel role for IL-13Rα2 as a negative regulator of both IL-13 and IL-4 signaling in human bronchial fibroblasts.

Clinical implications

It appears that IL-13Rα2 might be a powerful suppressor of TH2-mediated responses and thus represents a potential therapeutic target for the treatment of asthma.

Section snippets

Reagents

Eotaxin ELISA kit, recombinant shIL-4Rα and shIL-13Rα2.Fc, and anti-IL-13Rα2 antibody were obtained from R&D Systems (Abingdon, United Kingdom). Recombinant IL-13 and IL-4 were purchased from Peprotech (London, United Kingdom). A monoclonal anti-IL-13Rα2 from Diaclone (IDS, Boldon, Tyne and Wear, United Kingdom) was used for neutralization experiments and FACs assays, and an anti-IL-13Rα2 from R&D Systems was used for immunoprecipitation experiments.

Primary human cell culture

Bronchial fibroblasts were grown from

Neutralization of IL-13 by soluble IL-13Rα2

We first investigated the ability of a recombinant soluble form of IL-13Rα2 that lacked the transmembrane and cytoplasmic domain of the receptor (shIL-13Rα2) to attenuate responses to IL-13 or IL-4 in fibroblasts. Increasing amounts of shIL-13Rα2 were preincubated with IL-13 or IL-4 for 6 hours before being added to fibroblasts for 24 hours. The supernatants were then collected and assayed for eotaxin release by means of ELISA. Although soluble human IL-4 receptor α (shIL13Rα2) inhibited

Discussion

Many cytokines, such as IL-5, IL-6, and IL-9, have soluble receptors31 that modulate their functions. Production of these isoforms can occur either through alternative splicing or through proteolytic cleavage of the membrane-anchored protein from the cell surface. Although some soluble receptors, such as the soluble IL-6 receptor, are agonists, most soluble receptors are antagonists because they compete with their membrane counterparts for their ligands. In the present study we show that

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    Dr Andrews is funded by Asthma UK.

    Disclosure of potential conflict of interest: S. T. Holgate has consultant arrangements with and is on the speakers' bureau for Novartis. D. E. Davies has consultant arrangements with and owns stock in Synairgen. The rest of the authors declare that they have no conflict of interest.

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