Abstract
BackgroundTumor 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The tumor necrosis factor (TNF), first termed in 1962 [1], was initially known for its ability to induce programmed cell death or apoptosis
Tumor necrosis factor (TNF) binds to two types of outer membrane bound receptors on target cells, TNFR1 and TNFR2, and triggers the cell survival and proinflammatory Nuclear factor-κB (NF-κB) and Mitogen-activated protein (MAP) kinases activations [3]
TNFR1 signaling topology and model To develop a computational model of proinflammatory TNFR1 signaling dynamics, we first require the known signal transduction pathways
Summary
The tumor necrosis factor (TNF), first termed in 1962 [1], was initially known for its ability to induce programmed cell death or apoptosis. Throughout the years, the TNF has been intensely investigated for its anticancer property [2] Today, this cytokine is central to the regulation of myriad important cellular processes such as proliferation, differentiation, growth, and the immune response. The TNFR1 induces intracellular cell death pathways via caspases after internalization through endocytosis It is, conceivable that the dysregulation of the TNF signaling process will. 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. To effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted
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