IL-13Rα2 Membrane and Soluble Isoforms Differ in Humans and Mice

Although mice have nanogram per milliliter serum levels of soluble (s) IL-13R alpha 2, humans lack sIL-13R alpha 2 in serum. Our data provide a mechanism for this biological divergence. In mice, discrete transcripts encoding soluble and membrane forms of IL-13R alpha 2 are generated by alternative splicing. We used small interfering RNA to specifically deplete the transcript encoding membrane (mem) IL-13R alpha 2 (full-length) or sIL-13R alpha 2 (Delta Ex10) in murine cells. Depletion of the full-length transcript decreased memIL-13R alpha 2 but had no effect on the level of sIL-13R alpha 2 in cell supernatants at baseline or following cytokine stimulation. Depletion of the Delta Ex10 transcript decreased sIL-13R alpha 2 in supernatants at baseline and following stimulation. In contrast to mice, we were unable to find a transcript encoding sIL-13R alpha 2 in humans and siRNA-mediated depletion of full-length IL-13R alpha 2 decreased both sIL-13R alpha 2 and memIL-13R alpha 2 in human cells. Inhibition of matrix metalloproteinases (MMP)/MMP-8 abolished production of sIL-13R alpha 2 from human cells. Thus, sIL-13R alpha 2 is derived exclusively from the memIL-13R alpha 2 transcript in humans through MMPs/MMP-8 cleavage of memIL-13R alpha 2, supporting a limited role for sIL-13R alpha 2 in humans and highlighting the potential importance of memIL-13R alpha 2 in human immunity. These observations require consideration when results of murine IL-13 studies are applied to humans. The Journal of Immunology, 2009, 183: 7870-7876.