We have previously shown that IL-4δ2, a naturally occurring in humans and other species splice variant of IL-4, competes with IL-4 for receptor binding and inhibits some of IL-4 effects on lymphocytes and monocytes. Numerous groups reported that the levels and the ratio of IL-4δ2 and IL-4 mRNAs change in immune, inflammatory, and infectious diseases. It has been suggested that recombinant human (rh) IL-4δ2 can be used therapeutically to neutralize the harmful effects of excess IL-4 in vivo, although it was not clear whether IL-4δ2 mRNA expressing cells secrete IL-4δ2 protein. Transfection of HEK293 or Jurkat cells with IL-4δ2-encoding constructs resulted in IL-4δ2 protein secretion confirmed by LC/MS, ELISA, and Western blotting. To investigate whether IL-4δ2 has no independent activity and acts only as an inhibitor of IL-4, we overexpressed human IL-4δ2 in mouse lungs. Adenovirus-mediated gene delivery of IL-4δ2 caused lymphocytic infiltration similar to that in IL-4-overexpressing mice, as well as proinflammatory/Th1 changes in pulmonary milieu, with the induced levels of TNF-α, IL-1, IFN-γ, IL-12p40, and MCP-1 significantly exceeding those induced by gene delivery of IL-4. Germline deficiency of STAT6 had no effect, whereas deficiency of IL-4Rα significantly attenuated IL-4δ2-induced or IL-4-induced changes in the lungs. Stimulation of primary human T cells or PBMC, but not fibroblasts or A549 cells, with rhIL-4δ2 induced phosphorylation of Jak1, Jak3, and Tyk2, but not of STAT6. IL-4δ2 potently induced production of MCP-1 in human T cells and upregulated IL-4δ2 mRNA production in an autocrine fashion by several hundred fold. Thus, IL-4δ2 is secreted as a protein, acts as a potent autocrine regulator of inflammation and immunity in an IL-4Rα-dependent STAT6-independent fashion, and is a potential novel target for future therapies.