The actions of interleukin-4 (IL-4) in vivo are likely to be positively influenced by the expression of membrane IL-4 receptors (mIL-4R) on target cells and negatively by the concentration of soluble IL-4 receptors (sIL-4R) in the extracellular environment. Inasmuch as the two forms of the mouse IL-4R are differentially encoded by alternatively spliced mRNA transcripts, the purpose of this work was to determine how their expression is regulated by IL-4 and T cell activation and whether there is preferential expression of one type of transcript over the other. In this study, the expression of sIL-4R and mIL-4R transcripts was analyzed by a semiquantitative RT-PCR method in resting and mitogen-activated splenic cells. Irrespectively of the state of cell activation, IL-4 up-regulated the levels of both types of mRNA with similar kinetics and dose-response curves. In contrast, ConA failed to enhance the steady-state levels of sIL-4R or mIL-4R transcripts despite increased expression at the protein level, suggesting that sIL-4R expression is also regulated at levels other than transcription. Western blot analysis of supernatants of IL-4- and ConA-stimulated spleen cells substantiated the presence of sIL-4R molecules derived by translation of sIL-4R-specific transcripts, thus confirming the importance of this mechanism for the generation of sIL-4R molecules in normal cells. These results indicate that the sIL-4R- and mIL-4R-specific transcripts are normally regulated in a parallel manner and further suggest that expression of both forms of the IL-4R is controlled at multiple levels (i.e., transcriptional and posttranscriptional).