Restricted accessResearch articleFirst published online 2018-04
Interleukin-4 Enhances the Sensitivity of Human Monocytes to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Through Upregulation of Death Receptor 4
Interleukin (IL)-4 is generally thought to promote tumor cell growth and inhibit apoptosis. However, its role in characteristics of monocytic leukemia cells was rarely reported. In this study, we assessed the role of IL-4 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity of human monocytes. After incubation with IL-4 for 24 h, death receptor 4 (DR4) was significantly increased without downregulation of TRAIL decoy receptors and antiapoptotic proteins in THP-1 monocytes, and human primary monocytes and U-937 cells also exhibited increased TRAIL-induced apoptosis compared with control. Enhancement of TRAIL-mediated apoptosis by IL-4 was blocked by anti-DR4-neutralizing antibodies. Both upregulation of DR4 and enhancement of TRAIL-mediated apoptosis by IL-4 could be blocked by inhibitors of Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphoinositol 3-kinase (PI3K)/Akt, and extracellular signal-regulated kinase to varying degrees. Thus, our data demonstrated a novel effect on TRAIL sensitivity on monocytes and monocytic leukemia cells of IL-4 and suggested that it may be necessary to reconsider the impact of current therapies against IL-4, JAK/STAT, and PI3K/Akt pathways with regard to TRAIL sensitivity.
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References
1.
AnnesleyCE, BrownP. 2015. Novel agents for the treatment of childhood acute leukemia. Ther Adv Hematol, 6(2):61–79.
BaileyDP, KashyapM, MirmonsefP, BoutonLA, DomenJ, ZhuJ, DessyprisEN, RyanJJ. 2004. Interleukin-4 elicits apoptosis of developing mast cells via a Stat6-dependent mitochondrial pathway. Exp Hematol, 32(1):52–59.
4.
BrodyJR, CostantinoCL, BergerAC, SatoT, LisantiMP, YeoCJ, EmmonsRV, WitkiewiczAK. 2009. Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle, 8(12):1930–1934.
5.
ChenSM, SunH, LiuYF, MaJ, ZhangQT, ZhuJ, LiT. 2015. Expression of TRAIL and its receptor DR5 and their significance in acute leukemia cells. Genet Mol Res, 14(4):18562–18568.
6.
ChungH, VilaysaneA, LauA, StahlM, MorampudiV, Bondzi-SimpsonA, PlatnichJM, BraceyNA, FrenchMC, BeckPL, ChunJ, VallanceBA, MuruveDA. 2016. NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis. Cell Death Differ, 23(8):1331–1346.
7.
ConticelloC, PediniF, ZeunerA, PattiM, ZerilliM, StassiG, MessinaA, PeschleC, De MariaR. 2004. IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins. J Immunol, 172(9):5467–5477.
8.
de MiguelD, LemkeJ, AnelA, WalczakH, Martinez-LostaoL. 2016. Onto better TRAILs for cancer treatment. Cell Death Differ, 23(5):733–747.
9.
DhandapaniL, YueP, RamalingamSS, KhuriFR, SunSY. 2011. Retinoic acid enhances TRAIL-induced apoptosis in cancer cells by upregulating TRAIL receptor 1 expression. Cancer Res, 71(15):5245–5254.
10.
Di StefanoAB, IovinoF, LombardoY, EternoV, HogerT, DieliF, StassiG, TodaroM. 2010. Survivin is regulated by interleukin-4 in colon cancer stem cells. J Cell Physiol, 225(2):555–561.
11.
DrosopoulosKG, RobertsML, CermakL, SasazukiT, ShirasawaS, AnderaL, PintzasA. 2005. Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway. J Biol Chem, 280(24):22856–22867.
12.
DuJ, WangY, ChenD, JiG, MaQ, LiaoS, ZhengY, ZhangJ, HouY. 2016. BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-kappaB. Cancer Lett, 383(2):145–153.
13.
FranseckyL, MochmannLH, BaldusCD. 2015. Outlook on PI3K/AKT/mTOR inhibition in acute leukemia. Mol Cell Ther, 3:2.
14.
FurqanM, MukhiN, LeeB, LiuD. 2013. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res, 1(1):5.
GuanB, YueP, LotanR, SunSY. 2002. Evidence that the human death receptor 4 is regulated by activator protein 1. Oncogene, 21(20):3121–3129.
17.
IrmlerIM, GajdaM, BrauerR. 2007. Exacerbation of antigen-induced arthritis in IFN-gamma-deficient mice as a result of unrestricted IL-17 response. J Immunol, 179(9):6228–6236.
JinquanT, JacobiHH, JingC, MillnerA, StenE, HviidL, AntingL, RyderLP, GlueC, SkovPS, JarmanE, LamberthK, MallingHJ, PoulsenLK. 2003. CCR3 expression induced by IL-2 and IL-4 functioning as a death receptor for B cells. J Immunol, 171(4):1722–1731.
20.
JohnstoneRW, FrewAJ, SmythMJ. 2008. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer, 8(10):782–798.
21.
JonesDT, GaneshaguruK, MitchellWA, ForoniL, BakerRJ, PrenticeHG, MehtaAB, WickremasingheRG. 2003. Cytotoxic drugs enhance the ex vivo sensitivity of malignant cells from a subset of acute myeloid leukaemia patients to apoptosis induction by tumour necrosis factor receptor-related apoptosis-inducing ligand. Br J Haematol, 121(5):713–720.
22.
KatzJB, MullerAJ, PrendergastGC. 2008. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev, 222:206–221.
23.
KimSW, MoonJH, ParkSY. 2016. Activation of autophagic flux by epigallocatechin gallate mitigates TRAIL-induced tumor cell apoptosis via down-regulation of death receptors. Oncotarget, 7(40):65660–65668.
24.
LeeSO, LouW, HouM, OnateSA, GaoAC. 2003. Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway. Oncogene, 22(39):7981–7988.
25.
LiD, MengJ, YuN, JiaF, SunX, ZhangA, WangS, GaoF, JingY. 2011. Effect of IFN-gamma and IL-4 levels on the expression of Fas and Bcl-2 in peripheral blood lymphocytes in hemodialysis patients. J Artif Organs, 14(2):120–124.
26.
Manoury-SchwartzB, ChiocchiaG, BessisN, Abehsira-AmarO, BatteuxF, MullerS, HuangS, BoissierMC, FournierC. 1997. High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors. J Immunol, 158(11):5501–5506.
27.
MendozaFJ, IshdorjG, HuX, GibsonSB. 2008. Death receptor-4 (DR4) expression is regulated by transcription factor NF-kappaB in response to etoposide treatment. Apoptosis, 13(6):756–770.
28.
MonleonI, Martinez-LorenzoMJ, MonteagudoL, LasierraP, TaulesM, IturraldeM, PineiroA, LarradL, AlavaMA, NavalJ, AnelA. 2001. Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J Immunol, 167(12):6736–6744.
29.
MooreAS, KearnsPR, KnapperS, PearsonAD, ZwaanCM. 2013. Novel therapies for children with acute myeloid leukaemia. Leukemia, 27(7):1451–1460.
30.
NelmsK, KeeganAD, ZamoranoJ, RyanJJ, PaulWE. 1999. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol, 17:701–738.
31.
PaulWE. 2015. History of interleukin-4. Cytokine, 75(1):3–7.
32.
PhillipsTA, NiJ, PanG, RubenSM, WeiYF, PaceJL, HuntJS. 1999. TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege. J Immunol, 162(10):6053–6059.
33.
PrendergastGC. 2008. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene, 27(28):3889–3900.
34.
RiccioniR, PasquiniL, MarianiG, SaulleE, RossiniA, DiverioD, PelosiE, VitaleA, ChierichiniA, CedroneM, FoaR, Lo CocoF, PeschleC, TestaU. 2005. TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL. Haematologica, 90(5):612–624.
35.
RocaH, CraigMJ, YingC, VarsosZS, CzarnieskiP, AlvaAS, HernandezJ, FullerD, DaignaultS, HealyPN, PientaKJ. 2012. IL-4 induces proliferation in prostate cancer PC3 cells under nutrient-depletion stress through the activation of the JNK-pathway and survivin up-regulation. J Cell Biochem, 113(5):1569–1580.
36.
SarosiekKA, NechushtanH, LuX, RosenblattJD, LossosIS. 2009. Interleukin-4 distinctively modifies responses of germinal centre-like and activated B-cell-like diffuse large B-cell lymphomas to immuno-chemotherapy. Br J Haematol, 147(3):308–318.
37.
SecchieroP, ZerbinatiC, di IasioMG, MelloniE, TiribelliM, GrillV, ZauliG. 2007. Synergistic cytotoxic activity of recombinant TRAIL plus the non-genotoxic activator of the p53 pathway nutlin-3 in acute myeloid leukemia cells. Curr Drug Metab, 8(4):395–403.
38.
SteelmanLS, PohnertSC, SheltonJG, FranklinRA, BertrandFE, McCubreyJA. 2004. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 18(2):189–218.
39.
SungES, KimA, ParkJS, ChungJ, KwonMH, KimYS. 2010. Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells. Apoptosis, 15(10):1256–1269.
40.
TazzariPL, TabelliniG, RicciF, PapaV, BortulR, ChiariniF, EvangelistiC, MartinelliG, BontadiniA, CoccoL, McCubreyJA, MartelliAM. 2008. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res, 68(22):9394–9403.
41.
TodaroM, LombardoY, FrancipaneMG, AleaMP, CammareriP, IovinoF, Di StefanoAB, Di BernardoC, AgrusaA, CondorelliG, WalczakH, StassiG. 2008. Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ, 15(4):762–772.
42.
TrivediR, MishraDP. 2015. Trailing TRAIL resistance: novel targets for TRAIL sensitization in cancer cells. Front Oncol, 5:69.
43.
TsuchiyaS, YamabeM, YamaguchiY, KobayashiY, KonnoT, TadaK. 1980. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer, 26(2):171–176.
44.
Ul-HaqZ, NazS, MesaikMA. 2016. Interleukin-4 receptor signaling and its binding mechanism: a therapeutic insight from inhibitors tool box. Cytokine Growth Factor Rev, 32:3–15.
45.
WeiW, WangD, ShiJ, XiangY, ZhangY, LiuS, LiuY, ZhengD. 2010. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces chemotactic migration of monocytes via a death receptor 4-mediated RhoGTPase pathway. Mol Immunol, 47(15):2475–2484.
46.
WeryS, LetourneurM, BertoglioJ, PierreJ. 1996. Interleukin-4 induces activation of mitogen-activated protein kinase and phosphorylation of shc in human keratinocytes. J Biol Chem, 271(15):8529–8532.
47.
YaoW, OhYT, DengJ, YueP, DengL, HuangH, ZhouW, SunSY. 2016. Expression of death receptor 4 is positively regulated by MEK/ERK/AP-1 signaling and suppressed upon MEK inhibition. J Biol Chem, 291(41):21694–21702.
48.
ZaidiMR, MerlinoG. 2011. The two faces of interferon-gamma in cancer. Clin Cancer Res, 17(19):6118–6124.
