title: Interferon regulatory factor-4 activates IL-2 and IL-4 promoters in cooperation with c-Rel.
abstract: Interferon regulatory factor (IRF)-4 is a member of the IRF transcription factor family, whose expression is primarily restricted to lymphoid and myeloid cells. In T-cells, IRF-4 expression is induced by T-cell receptor (TCR) cross-linking or treatment with phorbol-12-myristate-13-acetate (PMA)/Ionomycin, and IRF-4 is thought to be a critical factor for various functions of T-cells. To elucidate the IRF-4 functions in human adult T-cell leukemia virus type 1 (HTLV-1)-infected T-cells, which constitutively express IRF-4, we isolated IRF-4-binding proteins from T-cells, using a tandem affinity purification (TAP)-mass spectrometry strategy. Fourteen proteins were identified in the IRF-4-binding complex, including endogenous IRF-4 and the nuclear factor-kappaB (NF-κB) family member, c-Rel. The specific association of IRF-4 with c-Rel was confirmed by immunoprecipitation experiments, and IRF-4 was shown to enhance the c-Rel-dependent binding and activation of the interleukin-4 (IL-4) promoter region. We also demonstrated that IL-2 production was also enhanced by exogenously-expressed IRF-4 and c-Rel in the presence of P/I, in T-cells, and that the optimal IL-2 and IL-4 productions in vivo was IRF-4-dependent using IRF-4-/- mice. These data provide molecular evidence to support the clinical observation that elevated expression of c-Rel and IRF-4 is associated with the prognosis in adult T-cell leukemia/lymphoma (ATLL) patients, and present possible targets for future gene therapy.
authors: Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors: Hisakazu
authors: H
authors: Shindo
authors: Kiyoshi
authors: K
authors: Yasui
authors: Kazuo
authors: K
authors: Yamamoto
authors: Kiri
authors: K
authors: Honma
authors: Katsuyuki
authors: K
authors: Yui
authors: Tomoko
authors: T
authors: Kohno
authors: Yuhua
authors: Y
authors: Ma
authors: Koon Jiew
authors: KJ
authors: Chua
authors: Yoshinao
authors: Y
authors: Kubo
authors: Hitoshi
authors: H
authors: Aihara
authors: Takashi
authors: T
authors: Ito
authors: Takeshi
authors: T
authors: Nagayasu
authors: Toshifumi
authors: T
authors: Matsuyama
authors: Hideki
authors: H
authors: Hayashi
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D020569:Proto-Oncogene Proteins c-rel / Q000737:chemistry / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D007376:Interleukin-2; D015847:Interleukin-4; D020569:Proto-Oncogene Proteins c-rel; D000099218:Interferon Regulatory Factor-4