Splice isoforms of human interleukin-4 are functionally active in mice in vivo

Interleukin-4 (IL-4) acts on cultured cells in a species-specific fashion, although several reports have suggested that human (h) IL-4 may be functionally active in rodents in vivo. The latter finding, if true, would not only offer possibilities for pre-clinical testing of novel hIL-4-targeting therapies in animals, but also suggests new opportunities for mechanistic studies of IL-4 and its receptors. Conventional IL-4 is encoded by four exons, whereas its poorly studied alternatively spliced isoform is encoded by exons 1, 3 and 4 (IL-4δ2). Replication-deficient adenovirus-mediated gene delivery of hIL-4 isoforms (hIL-4 or hIL-4δ2) to mouse lungs caused similar pulmonary infiltration of T and B lymphocytes, but not eosinophils. There were significant differences in the changes of pulmonary cytokine milieu induced by hIL-4 compared with hIL-4δ2, with hIL-4δ2 inducing higher levels of pro-inflammatory (tumour necrosis factor-α, IL-1, and monocyte chemotactic protein-1) and T helper type 1 (IL-12 and interferon-γ) cytokines. There was no elevation in endogenous mouse (m) IL-4 or mIL-4δ2 mRNAs, and germ-line deficiency of mIL-4 did not affect the degree of pulmonary infiltration. When combined with an ovalbumin model of asthma, hIL-4δ2 stimulated a greater accumulation of lymphocytes than did hIL-4. Pulmonary infiltration of lymphocytes induced by expression of hIL-4 or hIL-4δ2 was attenuated, but not completely abrogated, by germ-line deficiency of mIL-4Rα or murine signal transducer and activator of transcription 6, suggesting that these signalling molecules mediate the in vivo effects of hIL-4 isoforms in mice. These findings suggest that splice isoforms of human IL-4 are functionally active in vivo in mice, and partially share the effects of the corresponding species-specific isoforms.