Angiogenin is upregulated during the alloreactive immune response and has no effect on the T‑cell expansion phase, whereas it affects the contraction phase by inhibiting CD4+ T‑cell apoptosis

Eleftheriadis,Theodoros; Pissas,Georgios; Sounidaki,Maria; Antoniadis,Nikolaos; Antoniadi,Georgia; Liakopoulos,Vassilios; Stefanidis,Ioannis

doi:10.3892/etm.2016.3786

Angiogenin is upregulated during the alloreactive immune response and has no effect on the T‑cell expansion phase, whereas it affects the contraction phase by inhibiting CD4+ T‑cell apoptosis

Authors:
- Theodoros Eleftheriadis
- Georgios Pissas
- Maria Sounidaki
- Nikolaos Antoniadis
- Georgia Antoniadi
- Vassilios Liakopoulos
- Ioannis Stefanidis
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Affiliations: Department of Nephrology, University of Thessaly Medical School, 41110 Larissa, Greece, Organ Transplant Unit, Hippokration General Hospital, Aristotle University of Thessaloniki Medical School, 54642 Thessaloniki, Greece
Published online on: October 6, 2016 https://doi.org/10.3892/etm.2016.3786
Pages: 3471-3475

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Abstract

Under growth conditions, angiogenin is translocated into the nucleus, where it enhances ribosomal RNA transcription, facilitating increased protein synthesis and cellular proliferation. During stress conditions, angiogenin is sequestered in the cytoplasm, where it cleaves transfer RNA (tRNA) to produce tRNA‑derived, stress‑induced small RNAs (tiRNAs) that inhibit global protein synthesis, but increase the translation of anti‑apoptotic factors. In the present study, the role of angiogenin in the human alloreactive immune response was evaluated using mixed lymphocyte reactions (MLRs) and neamine, an inhibitor of angiogenin nuclear translocation. In MLRs, angiogenin production was significantly (P<0.001) increased compared with resting peripheral blood mononuclear cells. The addition of neamine had no effect on cell proliferation, but did significantly (P<0.001) increase expression of Bcl‑2‑associated X protein and protein levels of activated caspase‑3 in CD4+ T‑cells isolated from the MLRs, indicating that angiogenin reduces apoptosis. In conclusion, angiogenin is upregulated during the alloreactive immune response, in which it does not affect the T‑cell expansion phase, but inhibits the T‑cell contraction phase by protecting against CD4+ T‑cell apoptosis.

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1	Tsuji T, Sun Y, Kishimoto K, Olson KA, Liu S, Hirukawa S and Hu GF: Angiogenin is translocated to the nucleus of HeLa cells and is involved in ribosomal RNA transcription and cell proliferation. Cancer Res. 65:1352–1360. 2005. View Article : Google Scholar : PubMed/NCBI
2	Hirukawa S, Olson KA, Tsuji T and Hu GF: Neamine inhibits xenografic human tumor growth and angiogenesis in athymic mice. Clin Cancer Res. 11:8745–8752. 2005. View Article : Google Scholar : PubMed/NCBI
3	Fu H, Feng J, Liu Q, Sun F, Tie Y, Zhu J, Xing R, Sun Z and Zheng X: Stress induces tRNA cleavage by angiogenin in mammalian cells. FEBS Lett. 583:437–442. 2009. View Article : Google Scholar : PubMed/NCBI
4	Yamasaki S, Ivanov P, Hu GF and Anderson P: Angiogenin cleaves tRNA and promotes stress-induced translational repression. J Cell Biol. 185:35–42. 2009. View Article : Google Scholar : PubMed/NCBI
5	Emara MM, Ivanov P, Hickman T, Dawra N, Tisdale S, Kedersha N, Hu GF and Anderson P: Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced stress granule assembly. J Biol Chem. 285:10959–10968. 2010. View Article : Google Scholar : PubMed/NCBI
6	Li S and Hu GF: Emerging role of angiogenin in stress response and cell survival under adverse conditions. J Cell Physiol. 227:2822–2826. 2012. View Article : Google Scholar : PubMed/NCBI
7	Saikia M and Hatzoglou M: The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering novel mechanisms of stress response and effect on human health. J Biol Chem. 290:29761–29768. 2015. View Article : Google Scholar : PubMed/NCBI
8	Sadagopan S, Veettil MV, Chakraborty S, Sharma-Walia N, Paudel N, Bottero V and Chandran B: Angiogenin functionally interacts with p53 and regulates p53-mediated apoptosis and cell survival. Oncogene. 31:4835–4847. 2012. View Article : Google Scholar : PubMed/NCBI
9	Saikia M, Jobava R, Parisien M, Putnam A, Krokowski D, Gao XH, Guan BJ, Yuan Y, Jankowsky E, Feng Z, et al: Angiogenin-cleaved tRNA halves interact with cytochrome c, protecting cells from apoptosis during osmotic stress. Mol Cell Biol. 34:2450–2463. 2014. View Article : Google Scholar : PubMed/NCBI
10	Rybak SM, Fett JW, Yao QZ and Vallee BL: Angiogenin mRNA in human tumor and normal cells. Biochem Biophys Res Commun. 146:1240–1248. 1987. View Article : Google Scholar : PubMed/NCBI
11	Olson KA, Verselis SJ and Fett JW: Angiogenin is regulated in vivo as an acute phase protein. Biochem Biophys Res Commun. 242:480–483. 1998. View Article : Google Scholar : PubMed/NCBI
12	Eleftheriadis T, Antoniadi G, Liakopoulos V, Pissas G, Stefanidis I and Galaktidou G: Plasma angiogenin and vascular endothelial growth factor a among hemodialysis patients. Iran J Kidney Dis. 6:209–215. 2012.PubMed/NCBI
13	Lioté F, Champy R, Moenner M, Boval-Boizard B and Badet J: Elevated angiogenin levels in synovial fluid from patients with inflammatory arthritis and secretion of angiogenin by cultured synovial fibroblasts. Clin Exp Immunol. 132:163–168. 2003. View Article : Google Scholar : PubMed/NCBI
14	Brenner D, Krammer PH and Arnold R: Concepts of activated T cell death. Crit Rev Oncol Hematol. 66:52–64. 2008. View Article : Google Scholar : PubMed/NCBI
15	Sato T, Deiwick A, Raddatz G, Koyama K and Schlitt HJ: Interactions of allogeneic human mononuclear cells in the two-way mixed leucocyte culture (MLC): Influence of cell numbers, subpopulations and cyclosporin. Clin Exp Immunol. 115:301–308. 1999. View Article : Google Scholar : PubMed/NCBI
16	Ibaragi S, Yoshioka N, Li S, Hu MG, Hirukawa S, Sadow PM and Hu GF: Neamine inhibits prostate cancer growth by suppressing angiogenin-mediated rRNA transcription. Clin Cancer Res. 15:1981–1988. 2009. View Article : Google Scholar : PubMed/NCBI
17	Kishimoto K, Yoshida S, Ibaragi S, Yoshioka N, Hu GF and Sasaki A: Neamine inhibits oral cancer progression by suppressing angiogenin-mediated angiogenesis and cancer cell proliferation. Anticancer Res. 34:2113–2121. 2014.PubMed/NCBI
18	Liu YP, Hu GF and Wu YX: Neamine is preferential as an anti-prostate cancer reagent by inhibiting cell proliferation and angiogenesis, with lower toxicity than cis-platinum. Oncol Lett. 10:137–142. 2015.PubMed/NCBI
19	Wu D, Yu W, Kishikawa H, Folkerth RD, Iafrate AJ, Shen Y, Xin W, Sims K and Hu GF: Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol. 62:609–617. 2007. View Article : Google Scholar : PubMed/NCBI
20	Fadeel B and Orrenius S: Apoptosis: A basic biological phenomenon with wide-ranging implications in human disease. J Intern Med. 258:479–517. 2005. View Article : Google Scholar : PubMed/NCBI
21	Sherrill KW, Byrd MP, Van Eden ME and Lloyd RE: BCL-2 translation is mediated via internal ribosome entry during cell stress. J Biol Chem. 279:29066–29074. 2004. View Article : Google Scholar : PubMed/NCBI
22	Eleftheriadis T, Pissas G, Antoniadi G, Spanoulis A, Liakopoulos V and Stefanidis I: Indoleamine 2,3-dioxygenase increases p53 levels in alloreactive human T cells, and both indoleamine 2,3-dioxygenase and p53 suppress glucose uptake, glycolysis and proliferation. Int Immunol. 26:673–684. 2014. View Article : Google Scholar : PubMed/NCBI