title: Interleukin-12 improves cytotoxicity of natural killer cells via upregulated expression of NKG2D.
abstract: Natural killer (NK) cells are crucial components of the innate immune system, providing the first line of defense against infectious pathogens and tumors. Interleukin (IL)-12 is an interleukin produced primarily by antigen-presenting cells that play an essential role in the interaction between the innate and adaptive arms of immunity acting upon T and NK cells to generate cytotoxic lymphocytes. In the present study, we explored the effect of IL-12 upregulation on the NK receptor NKG2D and on the promotion of NK cell function. IL-12 enhanced the cytotoxicity of NK cells to different solid and hematological tumor cell lines and promoted interferon-gamma secretion by NK cells. The IL-12-induced cytolytic effect was dependent on the interaction of NKG2D with its ligand, MICA, because blockade of either protein attenuated the effect of IL-12 on NK cytolysis. Reverse transcriptase-polymerase chain reaction and fluorescence-activated cell sorting analyses indicated that IL-12 treatment increased NKG2D transcripts and surface expression in NK cells. Also, IL-12 augmented the expression of cytotoxic effector molecules, TRAIL and perforin, and the phosphorylation of STAT1, STAT4, and ERK1/2, which may also contribute to lysis by NK cells. These results are encouraging for the potential use of IL-12 as part of immunotherapy.
authors.affiliation: Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China. caizhangsd@yahoo.com.cn
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Jiafeng
authors.initials: J
authors.lastname: Niu
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Zhou
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases