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TGF-?1 expression in regulatory NK1.1-CD4+NKG2D+ T cells dependents on the PI3K-p85?/JNK, NF-?B and STAT3 pathways.

ABSTRACT: NK1.1-CD4+NKG2D+ cells exert their immune-regulatory function in tumor as an unconventional regulatory T cell subset through the production of TGF-?1; however, the molecular mechanisms involving with the activation of nuclear factors for TGF-?1 transcription remain unclear. Here we determined that the PI3K-p85? subunit was specifically activated in NK1.1-CD4+NKG2D+ cells following an 8-hour stimulation by sRAE-1 or ?-CD3/sRAE-1, subsequently leading to the activation of PI3K-p110, Akt, and JNK. On the contrary, ?-CD3/?-CD28 stimulation did not induce the activation of PI3K-p85 and JNK. Consequently, activation of the nuclear transcription factor AP-1 as a consequence of JNK activation regulated TGF-?1 expression in NK1.1-CD4+NKG2D+ cells. Furthermore, activation of NF-?B in NK1.1-CD4+NKG2D+ cells resulted from both protein kinase C activation downstream of TCR/CD3 signaling and PI3K activation induced by NKG2D engagement. The STAT3-Y705 phosphorylation, as activated by PI3K, under stimulations of the sRAE-1 or ?-CD3/sRAE-1 also contributed to the TGF-?1 expression in NK1.1-CD4+NKG2D+ cells. Moreover, ChIP assay confirmed that STAT3 was capable of binding with the promoter regions of TGF-?1. In conclusion, our data showed that the TGF-?1 transcription in NK1.1-CD4+NKG2D+ cells induced by sRAE-1 or ?-CD3/sRAE-1 was involved with the AP-1, NF-?B, and STAT3 signaling pathways; therefore, regulation of AP-1, NF-?B, and STAT3 activation may play important roles in the development and function of NK1.1-CD4+NKG2D+ cells.

SUBMITTER: Han S

PROVIDER: S-EPMC5883098 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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TGF-β1 expression in regulatory NK1.1-CD4+NKG2D+ T cells dependents on the PI3K-p85α/JNK, NF-κB and STAT3 pathways.

Han Sen S Ding Shizhen S Miao Xin X Lin Zhijie Z Lu Guotao G Xiao Weiming W Ding Yanbing Y Qian Li L Zhang Yu Y Jia Xiaoqin X Zhu Guoqiang G Gong Weijuan W

American journal of cancer research 20180301 3

NK1.1-CD4+NKG2D+ cells exert their immune-regulatory function in tumor as an unconventional regulatory T cell subset through the production of TGF-β1; however, the molecular mechanisms involving with the activation of nuclear factors for TGF-β1 transcription remain unclear. Here we determined that the PI3K-p85α subunit was specifically activated in NK1.1-CD4+NKG2D+ cells following an 8-hour stimulation by sRAE-1 or α-CD3/sRAE-1, s ...[more]

PMID: 29637003

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Project description:BackgroundMyc is a well known driver of lymphomagenesis, and Myc-activating chromosomal translocation is the recognized hallmark of Burkitt lymphoma, an aggressive form of non-Hodgkin's lymphoma. We developed a model that mimics this translocation event by inserting a mouse Myc cDNA gene into the immunoglobulin heavy chain locus, just upstream of the intronic Emu enhancer. These mice, designated iMyc E mu, readily develop B-cell lymphoma. To study the mechanism of Myc-induced lymphoma, we analyzed signaling pathways in lymphoblastic B-cell lymphomas (LBLs) from iMyc E mu mice, and an LBL-derived cell line, iMyc E mu-1.ResultsNuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMyc E mu mice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMyc E mu-1 cells suppressed growth and caused apoptosis, and the abrogation of NF-kappaB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-kappaB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMyc E mu-1 cells NF-kappaB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-kappaB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMyc E mu-1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMyc E mu-1 cell proliferation and caused apoptosis, via downregulation of NF-kappaB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-kappaB, STAT3 or/and PI3K inhibitors led to additive inhibition of iMyc E mu-1 cell proliferation, suggesting that these signaling pathways converge.ConclusionsOur findings support the notion that constitutive activation of NF-kappaB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-kappaB, STAT3 and PI3K in the development of iMyc E mu B-cell lymphomas.

Dataset Information

TGF-?1 expression in regulatory NK1.1-CD4+NKG2D+ T cells dependents on the PI3K-p85?/JNK, NF-?B and STAT3 pathways.

Publications

TGF-β1 expression in regulatory NK1.1<sup>-</sup>CD4<sup>+</sup>NKG2D<sup>+</sup> T cells dependents on the PI3K-p85α/JNK, NF-κB and STAT3 pathways.

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