title: A systems biology approach to suppress TNF-induced proinflammatory gene expressions.
abstract: BACKGROUND
  Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted.
  
  
  RESULTS
  We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired.
  
  
  CONCLUSIONS
  Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Vincent
authors.initials: V
authors.lastname: Piras
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.forename: Masaru
authors.initials: M
authors.lastname: Tomita
authors.affiliation: Institute for Advanced Biosciences, Keio University, 14-1 Baba-cho, Tsuruoka, Japan. kumar@ttck.keio.ac.jp.
authors.forename: Kumar
authors.initials: K
authors.lastname: Selvarajoo
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015870:Gene Expression; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D049490:Systems Biology; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C119724:AGFG1 protein, human; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D048069:Tumor Necrosis Factors; D048051:p38 Mitogen-Activated Protein Kinases