Distinct Roles of Transforming Growth Factor-β-activated Kinase 1 (TAK1)-c-Rel and Interferon Regulatory Factor 4 (IRF4) Pathways in Human T Cell Lymphotropic Virus 1-transformed T helper 17 Cells Producing Interleukin-9

Abstract

Investigation of helper T cell markers in HTLV-1-transformed cell lines demonstrated thatHuT-102 has an IL-9-producing Th17 phenotype. We confirmed the vital role of retinoic acid-related orphan receptor C, a Th17 transcription factor, in the expression of IL-17. Interferon regulatory factor 4 (IRF4), a transcription factor overexpressed in all HTLV-1-infected cells, regulated IL-17 and IL-9 concomitantly. We further demonstrated a novel pathway for the regulation of Tax-induced cytokines, IL-9 and IL-6, through TAK1-mediated nuclear accumulation of c-Rel. A microarray analysis for IRF4 knocked down HuT-102 cells showed a significant up-regulation in the set of genes related to Th1, mainly IFN-␥ and several transcription factors. T-bet and IRF1, but not STAT1 and IRF9, participated in counteracting the inhibitory effect of IRF4 on the production of IFN-␥. Finally, suppression of both IRF4 and c-Rel resulted in the reduced proliferation. Collectively, these findings indicate that TAK1-c-Rel and IRF4 pathways play distinct roles in the maintenance of IL-9-producing Th17 phenotype of HTLV-1-transformed cells.Human T cell lymphotropic virus 1 (HTLV-1) 2 infects 20 million people worldwide with 3% developing adult T cell leukemia (ATL), and a further 0.25-3% developing an inflammatory disease of the CNS known as HTLV-1-associated myelopathy/tropical spastic paraparesis (1, 2). ATL is an aggressive proliferation of mature activated CD4 ϩ T cells, usually showing very poor prognosis for treatment (3,4). Although the antiviral combination therapy with IFN-␣ and zidovudine (AZT) is considered a treatment for ATL, patients frequently suffer relapse. This relapse emphasizes the need for new therapeutic approaches and strategies.Clonal expansions of HTLV-1 result from the expression of the viral transactivator protein Tax, which is thought to be a key molecule of ATL onset. Tax has many pathological functions such as virus replication, immortalization of host cells, and the activation of several transcriptional factors and signal transduction molecules (5-7). We also have shown previously Tax-dependent constitutive activation of TAK1-MAPK and TAK1-IRF3 pathways (8, 9). IRF4, which is preferentially expressed in lymphoid cells, was first identified as a transcription factor that negatively regulates the activity of IFN-regulated genes and TLR signaling (10, 11). In 2007, Ramos et al. (12) showed that either IRF4 or c-Rel was overexpressed in antiviral-resistant ATL cells. On the other hand, IRF4 is reported to be emerging as a critical regulator of T-helper cell (Th) differentiation, playing an important role in both Th2 and Th17 development by controlling cytokine expression and apoptosis (13,14).Th1-, Th2-, and T regulatory cell-associated cytokines were shown previously to be detected in the serum from HTLV-1-infected patients (15). On the other hand, a study of T cells showed a close relationship between HTLV-1-associated myelopathy/tropical spastic paraparesis and both multiple sclerosis and experimental autoimmune enc...

Nuclear Factor of Activated T Cells 1 (NFAT1)-induced Permissive Chromatin Modification Facilitates Nuclear Factor-κB (NF-κB)-mediated Interleukin-9 (IL-9) Transactivation

“…Interestingly, the HTLV-transformed cell line Hut-102 has an IL-9-producing Th17 phenotype. It is shown that in this cell, specific knockdown of NF-B protein c-Rel results in reduced IL-9 production (77). We have also found that NFAT1-deficient Th17 cells have a defect in IL-9 expression (data not shown).…”

Polymorphic Nature of Human T-Cell Leukemia Virus Type 1 Particle Cores as Revealed through Characterization of a Chronically Infected Cell Line

“…Likewise, IRF4 was found to be constitutively expressed in ATL as opposed to nonlymphocytic HTLV-1 infection (48). A number of studies have linked activating mutations and high levels of expression of IRF4 with HTLV-1 infection, with IRF4 expression resulting in reduced expression levels of genes previously shown to be dysregulated in ATL cases (48)(49)(50)(51)(52)(53). As proviral integration was found in the 5= ends of both of these genes, it is possible that integration may alter gene expression and thus may have contributed to transformation or ATL.…”

Cisplatin‑induced non‑canonical endocytosis of EGFR via p38 phosphorylation of the C‑terminal region containing Ser‑1015 in non‑small cell lung cancer cells

“…Whole cell lysates were prepared as described previously (19). Cell lysates were resolved by SDS-PAGE and transferred to an Immobilon-P nylon membrane (EMD Millipore).…”