Nucleic Acids Research, 1994, Vol. 22, No. 11 2134-2142
© 1994
MOLECULAR BIOLOGY |
Cyclosporin A sensitivity of the NF-
B site of the IL2R
promoter in untransformed murine T cells
1Division of Tumor Virology, Dana-Farber Cancer Institute Boston, MA 02115 2Department of Pathology, Harvard Medical School Boston, MA 02115 3Department of Biology, Massachusetts Institute of Technology Cambridge, MA 02139 4Rosenstiel Center and Department of Biology, Brandeis University Waltham, MA, USA
*To whom correspodence should be addressed at: Vertex Pharmaceuticals, 40 Allston St., Cambridge, MA 02139,USA
Received January 19, 1994. Revised May 2, 1994. Accepted May 2, 1994.
We have investigated the characteristics of IL2R
gene induction in untransformed murine T cells. Induction of IL2R mRNA by TCR/CD3 ligands in a murine T cell clone and in short-term splenic T cell cultures was inhibited by protein synthesis inhibitors and by CsA. This result was contrary to previous observations in JURKAT T leukemia cells and human peripheral blood T cells, suggesting a difference in the mechanisms of IL2R gene induction in these different cell types. The CsA sensitivity of IL2R mRNA induction represented a direct effect on the TCR/CD3 response, and was not due to CsA-sensitive release of the lymphokines IL2 or tumour necrosis factor (TNF) and consequent lymphokine-mediated induction of IL2R mRNA. The NF-
B site of the IL2R promoter was essential for gene induction through the TCR/CD3 complex, and the induction of reporter plasmids containing multimers of this site was significantly inhibited by CsA. Northern blotting analysis indicated that while the p65 subunit of NF-B was constitutively expressed and not appreciably induced upon T cell activation, mRNA for the p105 precursor of p50 NF-B was induced in response to TCR/CD3 stimulation and this induction was sensitive to CsA. Electrophoretic mobility shift assays and antiserum against the p50 subunit of NF-B indicated that p50 was a component of the inducible nuclear complex that bound to the IL2R B site. Appearance of the kB-binding proteins was insensitive to CsA at early times after activation ({small tilde}15 min), but was partially sensitive to CsA at later times. Based on these results, we propose that the NF-B site of the IL2R promoter mediates at least part of the CsA sensitivity of IL2R gene induction in untransformed T cells, possibly because de novo synthesis of p105 NF-B is required for sustained IL2R expression.
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