Interferon-γ enhances promyelocytic leukemia protein expression in acute promyelocytic cells and cooperates with all-trans‑retinoic acid to induce maturation of NB4 and NB4-R1 cells

He,Pengcheng; Liu,Yanfeng; Zhang,Mei; Wang,Xiaoning; Xi,Jieying; Wu,Di; Li,Jing; Cao,Yunxin

doi:10.3892/etm.2012.488

Interferon-γ enhances promyelocytic leukemia protein expression in acute promyelocytic cells and cooperates with all-trans‑retinoic acid to induce maturation of NB4 and NB4-R1 cells

Authors:
- Pengcheng He
- Yanfeng Liu
- Mei Zhang
- Xiaoning Wang
- Jieying Xi
- Di Wu
- Jing Li
- Yunxin Cao
View Affiliations

Affiliations: Department of Hematology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: February 16, 2012 https://doi.org/10.3892/etm.2012.488
Pages: 776-780

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In order to investigate the effect and mechanisms of interferon (IFN)-γ in combination with all-trans-retinoic acid (ATRA) on NB4 cells [ATRA-sensitive acute promyelocytic leukemia (APL) cell line] and NB4-R1 cells (ATRA-resistant APL cell line) and to search for a novel approach to solve the problem of ATRA resistance in APL, we initially treated NB4 and NB4-R1 cells with IFN-γ, ATRA and IFN-γ in combination with ATRA, respectively. The cell proliferation was then tested by MTT assay, and the cell differentiation was tested through light microscopy, by NBT test and flow cytometry (FCM). The expression of promyelocytic leukemia (PML) protein was observed by indirect immune fluorescent test. Results showed that ATRA inhibited the growth of NB4 cells, however, it could not inhibit the growth of NB4-R1 cells. IFN-γ inhibited the growth of both NB4 and NB4-R1 cells. Meanwhile, the growth inhibition effect of IFN-γ in combination with ATRA on both NB4 and NB4-R1 cells was significantly stronger than that of any single drug treatment. The results of the NBT reduction test and CD11b antigen detection by FCM indicated that IFN-γ induces the differentiation of NB4 and NB4-R1 cells to some extent. Moreover, the maturation degree of both NB4 and NB4-R1 cells induced by IFN-γ in combination with ATRA was more significant than that of IFN-γ or ATRA alone. After treatment with IFN-γ, the number of fluorescent particles in NB4 and NB4-R1 cell nuclei was higher than those in the control group, which indicated that IFN-γ may induce the expression of PML protein. Together, IFN-γ augments the proliferation inhibition effect of ATRA on NB4 and NB4-R1 cells through enhancing the expression of PML protein. IFN-γ in combination with ATRA not only strengthens the induction differentiation effect of ATRA on NB4 cells, but also can partially induce the maturation of NB4-R1 cells with ATRA resistance.

View Figures

View References

1.	Wang Z and Chen Z: Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 111:2505–2515. 2008. View Article : Google Scholar : PubMed/NCBI
2.	Zhou GB, Zhang J, Wang ZY, Chen SJ and Chen Z: Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy. Philos Trans R Soc Lond B Biol Sci. 362:959–971. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Wang X, Yin Y, Ma P, et al: Apoptosis of human pancreatic carcinoma cells induced by all-trans retinoic acid and interferon. Chin J Cancer Res. 21:224–228. 2009. View Article : Google Scholar
4.	Park HH, Kim M, Lee BH, et al: Intracellular IL-4, IL-10, and IFN-gamma levels of leukemic cells and bone marrow T cells in acute leukemia. Ann Clin Lab Sci. 36:7–15. 2006.PubMed/NCBI
5.	Hoyer KK, Herling M, Bagrintseva K, et al: T cell leukemia-1 modulates TCR signal strength and IFN-gamma levels through phosphatidylinositol 3-kinase and protein kinase C pathway activation. J Immunol. 175:864–873. 2005. View Article : Google Scholar : PubMed/NCBI
6.	Montoro E, Lemus D, Echemendia M, et al: Comparative evaluation of the nitrate reduction assay, the MTT test, and the resazurin microtitre assay for drug susceptibility testing of clinical isolates of Mycobacterium tuberculosis. J Antimicrob Chemother. 55:500–505. 2005. View Article : Google Scholar : PubMed/NCBI
7.	Huang Y, Liu J, Wang LZ, Zhang WY and Zhu XZ: Neuroprotective effects of cyclooxygenase-2 inhibitor celecoxib against toxicity of LPS-stimulated macrophages toward motor neurons. Acta Pharmacol Sin. 26:952–958. 2005. View Article : Google Scholar : PubMed/NCBI
8.	Owen J, Bates J and Lewis S: Differential effects of nitroblue tetrazolium on the hemodynamic responses elicited by activation of alpha(1)-adrenoceptors and 5-HT(2) receptors in conscious rats. Eur J Pharmacol. 535:248–252. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Choi HS, Kim JW, Cha YN and Kim C: A quantitative nitroblue tetrazolium assay for determining intracellular superoxide anion production in phagocytic cells. J Immunoassay Immunochem. 27:31–44. 2006. View Article : Google Scholar : PubMed/NCBI
10.	Shi J, Zhang Y, Su JY, et al: Cytotoxicity of IFN-gamma-activated dendritic cells to freshly isolated acute myeloid leukemia cells. J Exp Hematol. 13:1071–1075. 2005.PubMed/NCBI
11.	Burchert A, Muller MC, Kostrewa P, et al: Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol. 28:1429–1435. 2010. View Article : Google Scholar : PubMed/NCBI
12.	Khoo TL, Vangsted AJ, Joshua D and Gibson J: Interferon-alpha in the treatment of multiple myeloma. Curr Drug Targets. 12:437–446. 2011.PubMed/NCBI
13.	Benz R, Stussi G and Fehr J: Interferon as an alternative to purine analogues in the treatment of hairy cell leukaemia. Brit J Haematol. 148:664–666. 2010. View Article : Google Scholar : PubMed/NCBI
14.	Gupta V, Yi QL, Brandwein J, et al: Role of all-trans-retinoic acid (ATRA) in the consolidation therapy of acute promyelocytic leukaemia (APL). Leukemia Res. 29:113–114. 2005. View Article : Google Scholar : PubMed/NCBI
15.	Buonamici S, Li D, Mikhail F, et al: EVI1 abrogates interferon-alpha response by selectively blocking PML induction. J Biol Chem. 280:428–436. 2005. View Article : Google Scholar : PubMed/NCBI
16.	Reineke EL and Kao HY: Targeting promyelocytic leukemia protein: a means to regulating PML nuclear bodies. Int Biol Sci. 5:366–376. 2009. View Article : Google Scholar : PubMed/NCBI
17.	Chelbi-Alix MK, Vidy A, El Bougrini J and Blondel D: Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies. J Interferon Cytokine Res. 26:271–280. 2006. View Article : Google Scholar : PubMed/NCBI
18.	Crowder C, Dahle O, Davis RE, Gabrielsen OS and Rudikoff S: PML mediates IFN-alpha-induced apoptosis in myeloma by regulating TRAIL induction. Blood. 105:1280–1287. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Dror N, Rave-Harel N, Burchert A, et al: Interferon regulatory factor-8 is indispensable for the expression of promyelocytic leukemia and the formation of nuclear bodies in myeloid cells. J Biol Chem. 282:5633–5640. 2007. View Article : Google Scholar : PubMed/NCBI
20.	Bernardi R, Papa A and Pandolfi PP: Regulation of apoptosis by PML and the PML-NBs. Oncogene. 27:6299–6312. 2008. View Article : Google Scholar : PubMed/NCBI
21.	Li L and He DL: Transfection of promyelocytic leukemia in retrovirus vector inhibits growth of human bladder cancer cells. Acta Pharmacol Sin. 26:610–615. 2005. View Article : Google Scholar : PubMed/NCBI
22.	Ravindranath Y, Gregory J and Feusner J: Treatment of acute promyelocytic leukemia by using all-trans retinoic acid (ATRA). Leukemia. 18:1576–1577. 2004.
23.	Gupta V, Yib QL, Brandwein J, et al: Clinico-biological features and prognostic significance of PML/RARalpha isoforms in adult patients with acute promyelocytic leukemia treated with all trans retinoic acid (ATRA) and chemotherapy. Leuk Lymphoma. 45:469–480. 2004. View Article : Google Scholar
24.	Zhang X, Yan X, Zhou Z, et al: Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science. 328:240–243. 2010.PubMed/NCBI
25.	Wang ZG, Delva L, Gaboli M, et al: Role of PML in cell growth and the retinoic acid pathway. Science. 279:1547–1551. 1998. View Article : Google Scholar : PubMed/NCBI
26.	Abreu ELR, Baruffi MR, de Lima AS, et al: The co-expression of PML/RAR alpha and AML1/ETO fusion genes is associated with ATRA resistance. Brit J Haematol. 128:407–409. 2005. View Article : Google Scholar : PubMed/NCBI
27.	Mueller BU, Pabst T, Fos J, et al: ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU. 1 expression. Blood. 107:3330–3338. 2006. View Article : Google Scholar : PubMed/NCBI
28.	Andrianifahanana M, Agrawal A, Singh AP, et al: Synergistic induction of the MUC4 mucin gene by interferon-gamma and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways. Oncogene. 24:6143–6154. 2005. View Article : Google Scholar
29.	Liu CH: Study on the synergic effect of all-trans retinoic acid combined with IFN-alpha on the proliferation and differentiation of HL-60 cells. Chin J Cell Mol Immunol. 21:637–639. 642:2005.PubMed/NCBI
30.	Gu ZM, Wu YL, Zhou MY, et al: Pharicin B stabilizes retinoic acid receptor-alpha and presents synergistic differentiation induction with ATRA in myeloid leukemic cells. Blood. 116:5289–5297. 2010. View Article : Google Scholar : PubMed/NCBI
31.	Wang J, Peng Y, Sun YW, et al: All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer. Gastroenterology. 130:747–758. 2006. View Article : Google Scholar : PubMed/NCBI