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IL-13R alpha 2 membrane and soluble isoforms differ in humans and mice
Weiguo Chen1, Umasundari Sivaprasad, Yasuhiro Tabata
1Division of Asthma Research, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|December 17, 2009
Summary
Mice produce soluble IL-13Ralpha2 via alternative splicing, but humans do not. Human soluble IL-13Ralpha2 is generated by MMP-8 cleavage of membrane IL-13Ralpha2, indicating species-specific differences in IL-13Ralpha2 function.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Soluble IL-13Ralpha2 (sIL-13Ralpha2) is present in mouse serum but absent in human serum.
- Understanding the molecular basis for this divergence is crucial for interpreting mouse model studies in human health.
Purpose of the Study:
- To elucidate the distinct mechanisms of sIL-13Ralpha2 generation in mice and humans.
- To investigate the role of alternative splicing and post-translational modification in IL-13Ralpha2 expression.
Main Methods:
- Utilized small interfering RNA (siRNA) to deplete specific IL-13Ralpha2 transcripts (full-length membrane and soluble forms) in murine and human cells.
- Analyzed protein levels in cell supernatants and on cell membranes.
- Investigated the role of matrix metalloproteinases (MMPs), specifically MMP-8, in sIL-13Ralpha2 production.
Main Results:
- In mice, alternative splicing generates distinct transcripts for membrane (mem) IL-13Ralpha2 and sIL-13Ralpha2.
- Depletion of the DeltaEx10 transcript (encoding sIL-13Ralpha2) reduced sIL-13Ralpha2 levels in mouse cells.
- In humans, only the full-length transcript was found; its depletion reduced both memIL-13Ralpha2 and sIL-13Ralpha2.
- MMP/MMP-8 inhibition abolished sIL-13Ralpha2 production in human cells, indicating cleavage of memIL-13Ralpha2.
Conclusions:
- Human sIL-13Ralpha2 is exclusively produced by MMP-8 mediated cleavage of memIL-13Ralpha2, unlike in mice where it arises from alternative splicing.
- These findings highlight significant species-specific differences in IL-13Ralpha2 biology.
- The limited role of sIL-13Ralpha2 in humans and the importance of memIL-13Ralpha2 in human immunity warrant careful consideration when extrapolating mouse study results to humans.
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