IL-13R alpha 2 membrane and soluble isoforms differ in humans and mice.
Although mice have nanogram per milliliter serum levels of soluble (s) IL-13Ralpha2, humans lack sIL-13Ralpha2 in serum. Our data provide a mechanism for this biological divergence. In mice, discrete transcripts encoding soluble and membrane forms of IL-13Ralpha2 are generated by alternative splicing. We used small interfering RNA to specifically deplete the transcript encoding membrane (mem) IL-13Ralpha2 (full-length) or sIL-13Ralpha2 (DeltaEx10) in murine cells. Depletion of the full-length transcript decreased memIL-13Ralpha2 but had no effect on the level of sIL-13Ralpha2 in cell supernatants at baseline or following cytokine stimulation. Depletion of the DeltaEx10 transcript decreased sIL-13Ralpha2 in supernatants at baseline and following stimulation. In contrast to mice, we were unable to find a transcript encoding sIL-13Ralpha2 in humans and siRNA-mediated depletion of full-length IL-13Ralpha2 decreased both sIL-13Ralpha2 and memIL-13Ralpha2 in human cells. Inhibition of matrix metalloproteinases (MMP)/MMP-8 abolished production of sIL-13Ralpha2 from human cells. Thus, sIL-13Ralpha2 is derived exclusively from the memIL-13Ralpha2 transcript in humans through MMPs/MMP-8 cleavage of memIL-13Ralpha2, supporting a limited role for sIL-13Ralpha2 in humans and highlighting the potential importance of memIL-13Ralpha2 in human immunity. These observations require consideration when results of murine IL-13 studies are applied to humans.
Chen
Weiguo
W
Division of Asthma Research, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Sivaprasad
Umasundari
U
Tabata
Yasuhiro
Y
Gibson
Aaron M
AM
Stier
Matthew T
MT
Finkelman
Fred D
FD
Hershey
Gurjit K Khurana
GK
D017398:Alternative Splicing / Q000276:immunology; D000818:Animals; D002460:Cell Line; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification; D008565:Membrane Proteins / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification; D012995:Solubility; D020298:U937 Cells
D053663:Interleukin-13 Receptor alpha2 Subunit; D008565:Membrane Proteins; D020033:Protein Isoforms