title: Gene expression profiling of the human natural killer cell response to Fc receptor activation: unique enhancement in the presence of interleukin-12.
abstract: BACKGROUND
  Traditionally, the CD56(dim)CD16(+) subset of Natural Killer (NK) cells has been thought to mediate cellular cytotoxicity with modest cytokine secretion capacity. However, studies have suggested that this subset may exert a more diverse array of immunological functions. There exists a lack of well-developed functional models to describe the behavior of activated NK cells, and the interactions between signaling pathways that facilitate effector functions are not well understood. In the present study, a combination of genome-wide microarray analyses and systems-level bioinformatics approaches were utilized to elucidate the transcriptional landscape of NK cells activated via interactions with antibody-coated targets in the presence of interleukin-12 (IL-12).
  
  
  METHODS
  We conducted differential gene expression analysis of CD56(dim)CD16(+) NK cells following FcR stimulation in the presence or absence of IL-12. Next, we functionally characterized gene sets according to patterns of gene expression and validated representative genes using RT-PCR. IPA was utilized for biological pathway analysis, and an enriched network of interacting genes was generated using GeneMANIA. Furthermore, PAJEK and the HITS algorithm were employed to identify important genes in the network according to betweeness centrality, hub, and authority node metrics.
  
  
  RESULTS
  Analyses revealed that CD56(dim)CD16(+) NK cells co-stimulated via the Fc receptor (FcR) and IL-12R led to the expression of a unique set of genes, including genes encoding cytotoxicity receptors, apoptotic proteins, intracellular signaling molecules, and cytokines that may mediate enhanced cytotoxicity and interactions with other immune cells within inflammatory tissues. Network analyses identified a novel set of connected key players, BATF, IRF4, TBX21, and IFNG, within an integrated network composed of differentially expressed genes in NK cells stimulated by various conditions (immobilized IgG, IL-12, or the combination of IgG and IL-12).
  
  
  CONCLUSIONS
  These results are the first to address the global mechanisms by which NK cells mediate their biological functions when encountering antibody-coated targets within inflammatory sites. Moreover, this study has identified a set of high-priority targets for subsequent investigation into strategies to combat cancer by enhancing the anti-tumor activity of CD56(dim)CD16(+) NK cells.
authors.affiliation: The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, USA. Amanda.Harper@osumc.edu.|Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, 43210, USA. Amanda.Harper@osumc.edu.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Campbell
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, 43210, USA. Kelly.Regan@osumc.edu.|Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. Kelly.Regan@osumc.edu.
authors.forename: Kelly
authors.initials: K
authors.lastname: Regan
authors.affiliation: The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, USA. Bhave.4@osu.edu.
authors.forename: Neela
authors.initials: N
authors.lastname: Bhave
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. Arka.Pattanayak@osumc.edu.
authors.forename: Arka
authors.initials: A
authors.lastname: Pattanayak
authors.affiliation: Department of Pediatrics, The Cleveland Clinic, Cleveland, OH, 44106, USA. rxpariha@txch.org.
authors.forename: Robin
authors.initials: R
authors.lastname: Parihar
authors.affiliation: The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, USA. Andrew.Stiff@osumc.edu.|Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, 43210, USA. Andrew.Stiff@osumc.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Stiff
authors.affiliation: The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, USA. Prashant.Trikha@osumc.edu.
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.affiliation: The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, USA. Steven.Scoville@osumc.edu.|Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, 43210, USA. Steven.Scoville@osumc.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Scoville
authors.affiliation: Division of Human Cancer Genetics, The Ohio State University, Columbus, OH, 43210, USA. Sandya.Liyanarachchi@osumc.edu.
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.affiliation: Departments of Oncology and Medicine, Wayne State University and Barbara Ann Karmanos Cancer Institute, Detroit, MI, 48201, USA. vidyakon@gmail.com.
authors.forename: Sri Vidya
authors.initials: SV
authors.lastname: Kondadasula
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. Omkar.Lele@osumc.edu.
authors.forename: Omkar
authors.initials: O
authors.lastname: Lele
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60611, USA. Ramana.Davuluri@northwestern.edu.
authors.forename: Ramana
authors.initials: R
authors.lastname: Davuluri
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. Philip.Payne@osumc.edu.
authors.forename: Philip R O
authors.initials: PR
authors.lastname: Payne
authors.affiliation: The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, USA. William.Carson@osumc.edu.|Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA. William.Carson@osumc.edu.|The Ohio State University College of Medicine, N924 Doan Hall, 410 West 10th Ave., Columbus, OH, 43210, USA. William.Carson@osumc.edu.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D053263:Gene Regulatory Networks / Q000187:drug effects; D023281:Genomics; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D018664:Interleukin-12 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011961:Receptors, Fc / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D007074:Immunoglobulin G; D011961:Receptors, Fc; D018664:Interleukin-12