Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: Evidence for the involvement of NF-κB

Naoki Mori, Fumihiko Shirakawa, Hiroko Shimizu, Shuichi Murakami, Susumu Oda, Ken Ichi Yamamoto, Sumiya Eto

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Abstract

Freshly isolated leukemic cells from patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-6 (IL-6) protein and mRNA. To clarify the mechanisms that lead to the activation of IL-6 gene in HTLV- I-infected cells, we first studied the regulatory regions in the IL-6 gene transcription by transfection of chloramphenicol acetyltransferase (CAT) reporter plasmids containing the IL-6 promoter. When transfected into HTLV- I-infected T-cell lines MT-2 and HUT-102, IL-6 promoter/CAT plasmids were strongly activated without any stimulation. By deletion analysis of 5' upstream region of IL-6 promoter, the DNA region between -73 and -59 bp from the transcription start site of IL-6 gene was important in the expression of IL-6/CAT activities in HTLV-I-infected cells. This region contains nuclear factor (NF)-κB binding site. The site-directed mutation of the κB motif in IL-6/CAT plasmid resulted in the complete abrogation of IL-6 promoter activity in these cells. Furthermore, when IL-6 promoter/CAT plasmid was introduced into an HTLV-I-uninfected T-cell line, Jurkat, IL-6 promoter activity was silent in the basal level, but strongly increased by the cotransfection with an HTLV-I tax expression plasmid. However, tax expression plasmid showed no transactivation activity, when κB site was mutated in IL- 6 promoter/CAT plasmid. We found that the IL-6 κB site specifically formed a complex with NF-κB-containing nuclear extracts from MT-2 and HUT-102 cells. Finally, transfection of HTLV-I tax into Jurkat cells resulted in induction of specific binding of nuclear extracts to the NF-κB sequence. These results strongly suggest that HTLV-I tax gene may transactivate IL-6 gene through κB site in HTLV-I-positive T-cell lines and activation of NF-κB may be crucial in HTLV-I-induced IL-6 gene activation in ATL.

Original languageEnglish
Pages (from-to)2904-2911
Number of pages8
JournalBlood
Volume84
Issue number9
Publication statusPublished - Nov 1 1994
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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