IL-2 dose regulates TNF-alpha mRNA transcription and protein secretion in human peripheral blood lymphocytes.
TNF-alpha is an inducible cytokine with widely divergent effects on numerous target tissues. Secretion and response to TNF-alpha 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-alpha has been implicated in a number of pathophysiologic processes involving lymphocytes. In this report, we have investigated the regulation of TNF-alpha in normal lymphocytes stimulated with IL-2. Our results demonstrate that the level of TNF-alpha gene expression can be determined by the quantity of IL-2 present during lymphocyte activation. The increased steady-state levels of TNF-alpha mRNA were attributable to an enhanced rate of nuclear transcription. TNF-alpha secretion increased with escalating IL-2 dose in parallel to that of mRNA production. The modulation of TNF-alpha 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.
Owen-Schaub
L B
LB
Department of Tumor Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
de Mars
M
M
Murphy
E C
EC
Grimm
E A
EA
D015152:Blotting, Northern; D002467:Cell Nucleus / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology*; D008214:Lymphocytes / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012636:Secretory Rate / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D007376:Interleukin-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha