title: Alternatively spliced variants of interleukin-4 promote inflammation differentially.
abstract: IL-4δ2 is a natural splice variant of IL-4 that lacks the region encoded by the second exon. Numerous reports have suggested that the expression levels of IL-4δ2 change in various diseases, especially those with pulmonary involvement, but the in vivo effects of this splice variant have never been studied. Replication-deficient, AdV-mediated gene delivery of mIL-4δ2 to mouse lungs in vivo was used, and the effects compared with similar adenoviral delivery of mIL-4 or with infection with a noncoding NULL viral construct. Overexpression of IL-4δ2 or IL-4 caused pulmonary infiltration by T and B lymphocytes, whereas in contrast to IL-4, IL-4δ2 did not induce eosinophilia or goblet cell hyperplasia. Microarray analysis of global gene expression revealed that IL-4δ2 and IL-4 had differential effects on gene expression. These splice variants also differentially regulated pulmonary levels of the cytokines TNF-α, eotaxin, IL-1α, IFN-γ, and MCP-1, whereas both tended to increase total lung collagen modestly. Pulmonary infiltration by lymphocytes in response to overexpression of IL-4δ2 was attenuated but not abrogated completely by germline deficiency of IL-4Rα or STAT6, whereas deficiency of endogenous IL-4 had no effect. Thus, IL-4δ2 promotes lymphocytic inflammation in vivo (although differentially from IL-4, in part), and the effects of IL-4δ2 are not mediated by endogenous IL-4. Differential targeting of IL-4δ2 and IL-4 may therefore be considered in developing future therapeutic agents.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
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: Kendrick
authors.initials: K
authors.lastname: Highsmith
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: D000256:Adenoviridae / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D020397:Goblet Cells / Q000473:pathology; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D008171:Lung Diseases / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D011956:Receptors, Cell Surface / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000502:physiology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D003094:Collagen; D016207:Cytokines; D015847:Interleukin-4; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C494100:Stat6 protein, mouse