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Vol. 287, Issue 3, 1105-1112, December 1998

Transforming Growth Factor-Beta 1 (TGF-beta 1) Promotes IL-2 mRNA Expression Through the Up-regulation of NF-kappa B, AP-1 and NF-AT in EL4 Cells1

Seung H. Han2, Sung Su Yea2, Young J. Jeon2, Kyu-H. Yang2 and Norbert E. Kaminski

Dept. of Pharmacology & Toxicology and the Dept. of Pathology, Michigan State University, East Lansing, Michigan

Transforming growth factor beta 1 (TGF-beta 1) has been previously shown to modulate interleukin 2 (IL-2) secretion by activated T-cells. In the present studies, we determined that TGF-beta 1 induced IL-2 mRNA expression in the murine T-cell line EL4, in the absence of other stimuli. IL-2 mRNA expression was significantly induced by TGF-beta 1 (0.1-1 ng/ml) over a relatively narrow concentration range, which led to the induction of IL-2 secretion. Under identical condition, we examined the effect of TGF-beta 1 on the activity of nuclear factor AT (NF-AT), nuclear factor kappa B (NF-kappa B), activator protein-1 (AP-1) and octamer, all of which contribute to the regulation of IL-2 gene expression. Electrophoretic mobility shift assays showed that TGF-beta 1 markedly increased NF-AT, NF-kappa B and AP-1 binding to their respective cognate DNA binding sites, whereas octamer binding remained constant, as compared with untreated cells. Employing a reporter gene expression system with p(NF-kappa B)3-CAT, p(NF-AT)3-CAT and p(AP-1)3-CAT, TGF-beta 1 treatment of transfected EL4 cells induced a dose-related increase in chloramphenicol acetyltransferase activity that correlated well with the DNA binding profile found in the electrophoretic mobility shift assay studies. These results show that TGF-beta 1, in the absence of any additional stimuli, up-regulates the activity of key transcription factors involved in IL-2 gene expression, including NF-AT, NF-kappa B and AP-1, to help promote IL-2 mRNA expression by EL4 cells.

0022-3565/98/2873-1105$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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