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

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 alpha 1 (IL-13R alpha 1) and IL-4 receptor a (IL,4R alpha). The nonsignaling receptor IL-13 receptor alpha 2 (IL-13R alpha 2) 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-13R alpha 2 on IL-13- and IL-4-mediated effects. Methods: Primary human fibroblasts were grown from endobronchial biopsy specimens obtained from volunteers. Upregulation of IL-13R alpha 2 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-13R alpha 2 blocked the effects of IL-13, but not IL-4, in fibroblasts in vitro. However, we found that the transmembrane form of IL-13Ra2 could attenuate both IL-13 and IL-4 responses, even though the response to TNF-alpha was unaffected. Furthermore, we found that IL-13R alpha 2 became associated with IL-4R alpha in the presence of IL-4. Addition of a blocking antibody to the extracellular domain of IL-13Ra2 restored responses of both IL-13 and IL-4. Conclusion: The ability of IL-13R alpha 2 to regulate IL-4 was previously unrecognized in primary airway cells. These data reveal a novel role for IL-13Roe2 as a negative regulator of both IL-13 and IL-4 signaling in human bronchial fibroblasts. Clinical implications: It appears that IL-13R alpha 2 might be a powerful suppressor of T(H)2-mediated responses and thus represents a potential therapeutic target for the treatment of asthma.