The rate of the degradation of Interleukin 2 (IL-2) mRNA produced In stimulated human tonsillar lymphocytes was found to be significantly decreased in cells continuously stimulated with a calcium lonophore, A23187, and a phorbol ester, phorbol 12, 13-dibutylate (PDB) as compared with that in unstimulated cells. When the lymphocytes were stimulated with A23187 and PDB, IL-2 mRNA reached a maximum level at 8 h and gradually decreased to almost the base line by 27 h. IL-2 mRNA produced was rapidly degraded when the stimulants were washed out at 12 h and the cells further cultured in the presence of actinomycln D, which stops mRNA synthesis. However, the stability of IL-2 mRNA was increased by the addition of PDB or A23187. A maximal effect was observed when both were added. The effect of PDB was dose-dependent and Inhibited by the inhibitors of protein kinase C (PKC), staurosporine, and K252a, suggesting the Involvement of PKC In the control of IL-2 mRNA stability. The involvement of protein phosphoryiatlon In the regulating mechanism of IL-2 mRNA stability was supported by the fact that the addition of okadalc acid, which inhibits serine/threonine protein phosphatases, resulted in an increase in the stability of IL-2 mRNA. Further study demonstrated that the rate of degradation of ³²P-labeled IL-2 mRNA, which was prepared by cell-free transcription of IL-2 cDNA, in the polysomal fraction obtained from PDB-stlmulated lymphocytes was decreased compared with that obtained from unstimulated lymphocytes. These results Indicate the presence of a mechanism controlling the stability of IL-2 mRNA that Is regulated by PKC.