title: Differential roles of constitutively activated ERK1/2 and NF-kappa B in cytotoxicity and proliferation by human NK cell lines.
abstract: Compared with freshly isolated peripheral blood natural killer (NK) cells, the YT and NK-92 cell lines are characterized by elevated cytolytic activity. The molecular mechanisms underlying the rapid proliferation and enhanced lytic activity of NK cell lines are poorly understood. Investigation of these cell lines revealed that ERK1/2 and NF-kappa B are constitutively activated, providing evidence that these two signaling pathways are differentially involved in cytolysis and proliferation. Furthermore, blocking ERK1/2 activation with the specific inhibitor, PD098059, inhibited cytolytic activity in both cell lines and reduced mRNA expression of cytolysis-related effector molecules such as Fas-L and IFN gamma, as measured by semi-quantitative RT-PCR. However, MTT colormetric analysis showed that treatment with the PD098059 inhibitor did not affect cell proliferation. Meanwhile, blockade of the NF-kappa B signaling pathway using MG132 inhibited cellular growth without impacting cytolytic capability. No synergistic interactions were observed between ERK1/2 and NF-kappa B after combination treatment with PD098059 and MG132, suggesting that these two signaling pathways likely affect cellular proliferation and cytotoxicity by NK cells differentially.
authors.affiliation: Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua Western Road, Jinan 250012, China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Liang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005419:Flavonoids; D007976:Leupeptins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one