Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2.

Abstract

Interleukin 1 (IL-1) has been obtained from the Epstein-Barr virus-infected B-lymphoblastoid cell line 3B6 and shown to be involved in autocrine growth of 3B6 B cells. Independently, adult T-cell leukemia-derived factor (ADF) was purified from human T-lymphotropic virus I-infected leukemic T-cell line (ATL-2) and reported as an interleukin 2 (IL-2) receptor-inducing factor. We have previously reported the same molecular mass, pI, and NH2-terminal amino acid sequence for both 3B6-derived IL-1 and ADF. cDNA cloning of ADF demonstrated high homology with the prokaryotic disulfide reducing enzyme thioredoxin. We show here that ADF and 3B6-derived IL-1 are identical. By RNA blot, 3B6 and ATL-2 cells were shown to contain high levels of 0.6-kilobase mRNA corresponding to ADF. Such message was not detected in resting peripheral blood lymphocytes but could be weakly induced by lymphocyte activation. Antibodies have been raised against synthetic peptides corresponding to the NH2 terminus and the COOH terminus of ADF. Immunoblotting and sequential immunoprecipitation with these antibodies revealed the same 13-kDa protein in 3B6 and ATL-2 cells. Recombinant ADF could sustain growth of 3B6 and ATL-2 cells at low cellular concentration without fetal calf serum; ADF, thus, appears involved in their autocrine growth. Similarly, recombinant ADF could enhance growth of other B-cell lines, including the Epstein-Barr virus-negative Burkitt lymphoma line BL41 and the lymphoblastoid cell lines CRAG8, CRB95, and 1G8. Finally, recombinant ADF exhibits marked synergism with other cytokines, such as IL-1 and IL-2, allowing virally infected lymphocytes to respond to suboptimal amounts of a variety of growth factors.

Cloning and sequencing of a human thioredoxin reductase

“…The transcription factor AP-1 (Fos/Jun heterodimer) is subject to redox control by the nuclear redox factor Ref-1 which, in turn, is reduced by thioredoxin [13]. Thioredoxin has also been found to stimulate the growth of a variety of normal and cancer cell lines in culture [14][15][16][17]. The redox activity of thioredoxin is essential for its cell growth stimulating activity [16,17] and thioredoxin may be reduced by a thioredoxin reductase on the surface of cells [17].…”

The high-resolution three-dimensional solution structures of the oxidized and reduced states of human thioredoxin

“…Thioredoxin acts as a hydrogen donor for reductive enzymes such as ribonucleotide reductase [4,5]; functions as a general reductant for disulfides in proteins including insulin, oxytocin, and fibrinogen [ 1 ]; and serves as a regulatory factor for enzymes or receptors in photosynthetic systems [6]. Specific activities associated with human thioredoxin include the induction of interleukin-2 receptor expression [7], autocrine growth factor properties [8], and the stimulation of the DNA-binding activity of the transcription factor NF-xB [9,10]. The mechanism of the redox-related functions of E. coli thioredoxin has been proposed to involve nucleophilic attack by the more reactive Cys32 thiolate anion on a disulfide-containing substrate, producing a mixeddisulfide intermediate, which is then attacked by the thiolate of Cys35 to yield a reduced substrate and free, oxidized thioredoxin [11].…”

Increased expression of human thioredoxin/adult T cell leukemia–derived factor in Sjögren's syndrome

“…It has since been identified in T cells of patients with adult T cell leukemia (ATL) who have evidence of infection by human T lymphotropic virus type I (HTLV-I) (19), and in HTLV-I-transformed T cells in vitro (20), as well as in EBV-immortalized B cells (21). ADF expression can also be induced by a variety of stresses, including x-ray and ultraviolet irradiation, hydrogen peroxide, mitogens, and phorbol myristate acetate (22).…”

“…The recombinant form of (rADF) enhances the activation and proliferation of lymphocytes (23). IL-2Wp55 and the low-affinity Fc receptor for IgE (CD23/Fc&II) are induced by rADF in sensitive cell lines (21,24). As with the IL-2R system in ATL, CD23/Fc&II is associated with a tyrosine kinase (25) and is overexpressed in B cell lines infected with EBV (21,25,26).…”

“…IL-2Wp55 and the low-affinity Fc receptor for IgE (CD23/Fc&II) are induced by rADF in sensitive cell lines (21,24). As with the IL-2R system in ATL, CD23/Fc&II is associated with a tyrosine kinase (25) and is overexpressed in B cell lines infected with EBV (21,25,26). Previous data indicate that the transfection of ADF complementary DNA (cDNA) into YT cells, a line of human large granular lymphocytes, enhances promoter activity in the IL-2Wp55 system, perhaps via interaction with nuclear factor KB (NF-KB) (22).…”