IL-13 receptor alpha 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-13Ralpha1) and IL-4 receptor alpha (IL-4Ralpha). The nonsignaling receptor IL-13 receptor alpha 2 (IL-13Ralpha2) 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-13Ralpha2 on IL-13- and IL-4-mediated effects.


METHODS
Primary human fibroblasts were grown from endobronchial biopsy specimens obtained from volunteers. Upregulation of IL-13Ralpha2 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-13Ralpha2 blocked the effects of IL-13, but not IL-4, in fibroblasts in vitro. However, we found that the transmembrane form of IL-13Ralpha2 could attenuate both IL-13 and IL-4 responses, even though the response to TNF-alpha was unaffected. Furthermore, we found that IL-13Ralpha2 became associated with IL-4Ralpha in the presence of IL-4. Addition of a blocking antibody to the extracellular domain of IL-13Ralpha2 restored responses of both IL-13 and IL-4.


CONCLUSIONS
The ability of IL-13Ralpha2 to regulate IL-4 was previously unrecognized in primary airway cells. These data reveal a novel role for IL-13Ralpha2 as a negative regulator of both IL-13 and IL-4 signaling in human bronchial fibroblasts.


CONCLUSIONS
It appears that IL-13Ralpha2 might be a powerful suppressor of TH2-mediated responses and thus represents a potential therapeutic target for the treatment of asthma.
Andrews
Allison-Lynn
AL
Brooke Laboratories, Division of Infection, Inflammation, and Repair, UK.
Nasir
Tosia
T
Bucchieri
Fabio
F
Holloway
John W
JW
Holgate
Stephen T
ST
Davies
Donna E
DE
D001980:Bronchi / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D053660:Receptors, Interleukin-13 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation
D018793:Interleukin-13; D012333:RNA, Messenger; D053660:Receptors, Interleukin-13; D015847:Interleukin-4