IL-2 dose regulates TNF-α mRNA transcription and protein secretion in human peripheral blood lymphocytes

TNF-α is an inducible cytokine with widely divergent effects on numerous target tissues. Secretion and response to TNF-α appear to be required in cellular immune function including that of classical cytotoxic T cell development, non-MHC restricted cytotoxicity, and the mixed lymphocyte reaction. In addition, production of TNF-α has been implicated in a number of pathophysiologic processes involving lymphocytes. In this report, we have investigated the regulation of TNF-α in normal lymphocytes stimulated with IL-2. Our results demonstrate that the level of TNF-α gene expression can be determined by the quantity of IL-2 present during lymphocyte activation. The increased steady-state levels of TNF-α mRNA were attributable to an enhanced rate of nuclear transcription. TNF-α secretion increased with escalating IL-2 dose in parallel to that of mRNA production. The modulation of TNF-α gene expression by IL-2 concentration has been previously unrecognized and may be an important mechanism in normal immunohomeostasis, cellular dysregulations involving TNF production, and the dose-dependent toxicities observed with high-dose IL-2 immunotherapy.