Alternatively spliced variants of interleukin-4 promote inflammation differentially

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.