title: Splice isoforms of human interleukin-4 are functionally active in mice in vivo.
abstract: 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.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. iluzina@umaryland.edu
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.forename: Virginia
authors.initials: V
authors.lastname: Lockatell
authors.forename: Nevins W
authors.initials: NW
authors.lastname: Todd
authors.forename: Achsah D
authors.initials: AD
authors.lastname: Keegan
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity
chemical_list: D020033:Protein Isoforms; D015847:Interleukin-4